TY  - JOUR
AU  - Iturbide Martinez De Albeniz, A.
AU  - Ruiz Tejada Segura, M.L.
AU  - Noll, C.
AU  - Schorpp, K.K.
AU  - Rothenaigner, I.
AU  - Ruiz-Morales, E.R.
AU  - Lubatti, G.
AU  - Agami, A.
AU  - Hadian, K.
AU  - Scialdone, A.
AU  - Torres-Padilla, M.E.
C1  - 75456
C2  - 58013
SP  - 2128-2129
TI  - Addendum: Retinoic acid signaling is critical during the totipotency window in early mammalian development.
JO  - Nat. Struct. Mol. Biol.
VL  - 32
IS  - 10
PY  - 2025
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Correction to: Nature Structural & Molecular Biologyhttps://doi.org/10.1038/s41594-024-01341-3, published online 25 June 2024. In the version of the article initially published, the sentence "We acknowledge the European Synchrotron Radiation Facility and the Deutsches Elektronen-Synchrotron for provision of synchrotron radiation facilities and we would like to thank the staff of the ESRF and EMBL Grenoble at beamline MASSIF-1, and DESY and EMBL Hamburg at beamline P13, respectively, for assistance and support” was missing from the Acknowledgements section and has now been added to the HTML and PDF versions of the article.
AU  - Throll, P.*
AU  - G Dolce, L.*
AU  - Rico-Lastres, P.
AU  - Arnold, K.
AU  - Tengo, L.*
AU  - Basu, S.*
AU  - Kaiser, S.*
AU  - Schneider, R.
AU  - Kowalinski, E.*
C1  - 73299
C2  - 56989
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Author Correction: Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase.
JO  - Nat. Struct. Mol. Biol.
VL  - 32
PB  - Nature Portfolio
PY  - 2025
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Methylation of cytosine 32 in the anticodon loop of tRNAs to 3-methylcytosine (m3C) is crucial for cellular translation fidelity. Misregulation of the RNA methyltransferases setting this modification can cause aggressive cancers and metabolic disturbances. Here, we report the cryo-electron microscopy structure of the human m3C tRNA methyltransferase METTL6 in complex with seryl-tRNA synthetase (SerRS) and their common substrate tRNASer. Through the complex structure, we identify the tRNA-binding domain of METTL6. We show that SerRS acts as the tRNASer substrate selection factor for METTL6. We demonstrate that SerRS augments the methylation activity of METTL6 and that direct contacts between METTL6 and SerRS are necessary for efficient tRNASer methylation. Finally, on the basis of the structure of METTL6 in complex with SerRS and tRNASer, we postulate a universal tRNA-binding mode for m3C RNA methyltransferases, including METTL2 and METTL8, suggesting that these mammalian paralogs use similar ways to engage their respective tRNA substrates and cofactors.
AU  - Throll, P.*
AU  - G Dolce, L.*
AU  - Rico-Lastres, P.
AU  - Arnold, K.
AU  - Tengo, L.*
AU  - Basu, S.*
AU  - Kaiser, S.*
AU  - Schneider, R.
AU  - Kowalinski, E.*
C1  - 70922
C2  - 55820
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
TI  - Structural basis of tRNA recognition by the m3C RNA methyltransferase METTL6 in complex with SerRS seryl-tRNA synthetase.
JO  - Nat. Struct. Mol. Biol.
PB  - Nature Portfolio
PY  - 2024
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Integrin affinity regulation, also termed integrin activation, is essential for metazoan life. Although talin and kindlin binding to the β-integrin cytoplasmic tail is indispensable for integrin activation, it is unknown how they achieve this function. By combining NMR, biochemistry and cell biology techniques, we found that talin and kindlin binding to the β-tail can induce a conformational change that increases talin affinity and decreases kindlin affinity toward it. We also discovered that this asymmetric affinity regulation is accompanied by a direct interaction between talin and kindlin, which promotes simultaneous binding of talin and kindlin to β-tails. Disrupting allosteric communication between the β-tail-binding sites of talin and kindlin or their direct interaction in cells severely compromised integrin functions. These data show how talin and kindlin cooperate to generate a small but critical population of ternary talin-β-integrin-kindlin complexes with high talin-integrin affinity and high dynamics.
AU  - Aretz, J.*
AU  - Aziz, M.
AU  - Strohmeyer, N.*
AU  - Sattler, M.
AU  - Fässler, R.*
C1  - 68979
C2  - 53795
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1913-1924
TI  - Talin and kindlin use integrin tail allostery and direct binding to activate integrins.
JO  - Nat. Struct. Mol. Biol.
VL  - 30
IS  - 12
PB  - Nature Portfolio
PY  - 2023
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - To understand how the nucleosome remodeling and deacetylase (NuRD) complex regulates enhancers and enhancer–promoter interactions, we have developed an approach to segment and extract key biophysical parameters from live-cell three-dimensional single-molecule trajectories. Unexpectedly, this has revealed that NuRD binds to chromatin for minutes, decompacts chromatin structure and increases enhancer dynamics. We also uncovered a rare fast-diffusing state of enhancers and found that NuRD restricts the time spent in this state. Hi-C and Cut&Run experiments revealed that NuRD modulates enhancer–promoter interactions in active chromatin, allowing them to contact each other over longer distances. Furthermore, NuRD leads to a marked redistribution of CTCF and, in particular, cohesin. We propose that NuRD promotes a decondensed chromatin environment, where enhancers and promoters can contact each other over longer distances, and where the resetting of enhancer–promoter interactions brought about by the fast decondensed chromatin motions is reduced, leading to more stable, long-lived enhancer–promoter relationships.
AU  - Basu, S.*
AU  - Shukron, O.*
AU  - Hall, D.*
AU  - Parutto, P.*
AU  - Ponjavic, A.*
AU  - Shah, D.*
AU  - Boucher, W.*
AU  - Lando, D.*
AU  - Zhang, W.*
AU  - Reynolds, N.*
AU  - Sober, L.H.*
AU  - Jartseva, A.*
AU  - Ragheb, R.*
AU  - Ma, X.*
AU  - Cramard, J.*
AU  - Floyd, R.*
AU  - Balmer, J.*
AU  - Drury, T.A.*
AU  - Carr, A.R.*
AU  - Needham, L.M.*
AU  - Aubert, A.*
AU  - Communie, G.*
AU  - Gor, K.*
AU  - Steindel, M.*
AU  - Morey, L.*
AU  - Blanco, E.*
AU  - Bartke, T.
AU  - di Croce, L.*
AU  - Berger, I.*
AU  - Schaffitzel, C.*
AU  - Lee, S.F.*
AU  - Stevens, T.J.*
AU  - Klenerman, D.*
AU  - Hendrich, B.D.*
AU  - Holcman, D.*
AU  - Laue, E.D.*
C1  - 68200
C2  - 54824
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1628-1639
TI  - Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD.
JO  - Nat. Struct. Mol. Biol.
VL  - 30
IS  - 11
PB  - Nature Portfolio
PY  - 2023
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Correction to: Nature Structural & Molecular Biology, published online 28 September 2023. In the version of the article initially published there were some errors in the affiliations. A. Ponjavic’s second and third affiliations have been corrected to Present address: School of Physics and Astronomy, University of Leeds, Leeds, UK and Present address: School of Food Science and Nutrition, University of Leeds, Leeds, UK; and L. Morey now has only two affiliations: Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain and Present address: Sylvester Comprehensive Cancer Center, Department of Human Genetics, University of Miami Miller School of Medicine, Biomedical Research Building, Miami, FL, USA. Additionally, the received date has been corrected to 14 April 2020 from 26 October 2021. These errors have been corrected in the HTML and PDF versions of the article.
AU  - Basu, S.*
AU  - Shukron, O.*
AU  - Hall, D.W.*
AU  - Parutto, P.*
AU  - Ponjavic, A.*
AU  - Shah, D.I.*
AU  - Boucher, W.*
AU  - Lando, D.*
AU  - Zhang, W.*
AU  - Reynolds, N.*
AU  - Sober, L.H.*
AU  - Jartseva, A.*
AU  - Ragheb, R.*
AU  - Ma, X.*
AU  - Cramard, J.*
AU  - Floyd, R.*
AU  - Balmer, J.*
AU  - Drury, T.A.*
AU  - Carr, A.R.*
AU  - Needham, L.M.*
AU  - Aubert, A.*
AU  - Communie, G.*
AU  - Gor, K.*
AU  - Steindel, M.*
AU  - Morey, L.*
AU  - Blanco, E.*
AU  - Bartke, T.
AU  - di Croce, L.*
AU  - Berger, I.*
AU  - Schaffitzel, C.*
AU  - Lee, S.F.*
AU  - Stevens, T.J.*
AU  - Klenerman, D.*
AU  - Hendrich, B.D.*
AU  - Holcman, D.*
AU  - Laue, E.D.*
C1  - 68970
C2  - 53894
TI  - Publisher Correction: Live-cell three-dimensional single-molecule tracking reveals modulation of enhancer dynamics by NuRD.
JO  - Nat. Struct. Mol. Biol.
PY  - 2023
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Triose phosphates (TPs) are the primary products of photosynthetic CO2 fixation in chloroplasts, which need to be exported into the cytosol across the chloroplast inner envelope (IE) and outer envelope (OE) membranes to sustain plant growth. While transport across the IE is well understood, the mode of action of the transporters in the OE remains unclear. Here we present the high-resolution nuclear magnetic resonance (NMR) structure of the outer envelope protein 21 (OEP21) from garden pea, the main exit pore for TPs in C3 plants. OEP21 is a cone-shaped β-barrel pore with a highly positively charged interior that enables binding and translocation of negatively charged metabolites in a competitive manner, up to a size of ~1 kDa. ATP stabilizes the channel and keeps it in an open state. Despite the broad substrate selectivity of OEP21, these results suggest that control of metabolite transport across the OE might be possible.
AU  - Günsel, U.
AU  - Klöpfer, K.*
AU  - Häusler, E.
AU  - Hitzenberger, M.*
AU  - Bölter, B.*
AU  - Sperl, L.E.*
AU  - Zacharias, M.*
AU  - Soll, J.*
AU  - Hagn, F.
C1  - 67759
C2  - 54237
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 761-769
TI  - Structural basis of metabolite transport by the chloroplast outer envelope channel OEP21.
JO  - Nat. Struct. Mol. Biol.
VL  - 30
IS  - 6
PB  - Nature Portfolio
PY  - 2023
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Ferroptosis, marked by iron-dependent lipid peroxidation, may present an Achilles heel for the treatment of cancers. Ferroptosis suppressor protein-1 (FSP1), as the second ferroptosis mainstay, efficiently prevents lipid peroxidation via NAD(P)H-dependent reduction of quinones. Because its molecular mechanisms have remained obscure, we studied numerous FSP1 mutations present in cancer or identified by untargeted random mutagenesis. This mutational analysis elucidates the FAD/NAD(P)H-binding site and proton-transfer function of FSP1, which emerged to be evolutionarily conserved among different NADH quinone reductases. Using random mutagenesis screens, we uncover the mechanism of action of next-generation FSP1 inhibitors. Our studies identify the binding pocket of the first FSP1 inhibitor, iFSP1, and introduce the first species-independent FSP1 inhibitor, targeting the NAD(P)H-binding pocket. Conclusively, our study provides new insights into the molecular functions of FSP1 and enables the rational design of FSP1 inhibitors targeting cancer cells.
AU  - Nakamura, T.
AU  - Mishima, E.
AU  - Yamada, N.
AU  - Mourao, A.
AU  - Trümbach, D.
AU  - Doll, S.
AU  - Wanninger, J.
AU  - Lytton, E.
AU  - Sennhenn, P.*
AU  - Nishida Xavier da Silva, T.*
AU  - Angeli, J.P.F.*
AU  - Sattler, M.
AU  - Proneth, B.
AU  - Conrad, M.
C1  - 68749
C2  - 54959
SP  - 1806-1815
TI  - Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation.
JO  - Nat. Struct. Mol. Biol.
VL  - 30
IS  - 11
PY  - 2023
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - To maintain stable DNA concentrations, proliferating cells need to coordinate DNA replication with cell growth. For nuclear DNA, eukaryotic cells achieve this by coupling DNA replication to cell-cycle progression, ensuring that DNA is doubled exactly once per cell cycle. By contrast, mitochondrial DNA replication is typically not strictly coupled to the cell cycle, leaving the open question of how cells maintain the correct amount of mitochondrial DNA during cell growth. Here, we show that in budding yeast, mitochondrial DNA copy number increases with cell volume, both in asynchronously cycling populations and during G1 arrest. Our findings suggest that cell-volume-dependent mitochondrial DNA maintenance is achieved through nuclear-encoded limiting factors, including the mitochondrial DNA polymerase Mip1 and the packaging factor Abf2, whose amount increases in proportion to cell volume. By directly linking mitochondrial DNA maintenance to nuclear protein synthesis and thus cell growth, constant mitochondrial DNA concentrations can be robustly maintained without a need for cell-cycle-dependent regulation.
AU  - Seel, A.
AU  - Padovani, F.
AU  - Mayer, M.*
AU  - Finster, A.
AU  - Bureik, D.
AU  - Thoma, F.*
AU  - Osman, C.*
AU  - Klecker, T.*
AU  - Schmoller, K.M.
C1  - 68315
C2  - 54725
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 1549-1560
TI  - Regulation with cell size ensures mitochondrial DNA homeostasis during cell growth.
JO  - Nat. Struct. Mol. Biol.
VL  - 30
IS  - 10
PB  - Nature Portfolio
PY  - 2023
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - In the version of this article initially published, the surname of author Mayra L. Ruiz Tejada Segura was misspelled as Ruiz Tejeda Segura. The error has been corrected in the online version of the article.
AU  - Iturbide Martinez De Albeniz, A.
AU  - Ruiz Tejada Segura, M.L.
AU  - Noll, C.
AU  - Schorpp, K.K.
AU  - Rothenaigner, I.
AU  - Lubatti, G.
AU  - Agami, A.
AU  - Hadian, K.
AU  - Scialdone, A.
AU  - Torres-Padilla, M.E.
C1  - 64366
C2  - 51939
TI  - Author Correction: Retinoic acid signaling is critical during the totipotency window in early mammalian development.
JO  - Nat. Struct. Mol. Biol.
VL  - 29
IS  - 3
PY  - 2022
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Totipotent cells hold enormous potential for regenerative medicine. Thus, the development of cellular models recapitulating totipotent-like features is of paramount importance. Cells resembling the totipotent cells of early embryos arise spontaneously in mouse embryonic stem (ES) cell cultures. Such ‘2-cell-like-cells’ (2CLCs) recapitulate 2-cell-stage features and display expanded cell potential. Here, we used 2CLCs to perform a small-molecule screen to identify new pathways regulating the 2-cell-stage program. We identified retinoids as robust inducers of 2CLCs and the retinoic acid (RA)-signaling pathway as a key component of the regulatory circuitry of totipotent cells in embryos. Using single-cell RNA-seq, we reveal the transcriptional dynamics of 2CLC reprogramming and show that ES cells undergo distinct cellular trajectories in response to RA. Importantly, endogenous RA activity in early embryos is essential for zygotic genome activation and developmental progression. Overall, our data shed light on the gene regulatory networks controlling cellular plasticity and the totipotency program.
AU  - Iturbide Martinez De Albeniz, A.
AU  - Ruiz Tejada Segura, M.L.
AU  - Noll, C.
AU  - Schorpp, K.K.
AU  - Rothenaigner, I.
AU  - Ruiz-Morales, E.R.
AU  - Lubatti, G.
AU  - Agami, A.
AU  - Hadian, K.
AU  - Scialdone, A.
AU  - Torres-Padilla, M.E.
C1  - 62150
C2  - 50683
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 521-532
TI  - Retinoic acid signaling is critical during the totipotency window in early mammalian development.
JO  - Nat. Struct. Mol. Biol.
VL  - 28
IS  - 6
PB  - Nature Research
PY  - 2021
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - The prevalent model for cataract formation in the eye lens posits that damaged crystallin proteins form light-scattering aggregates. The α-crystallins are thought to counteract this process as chaperones by sequestering misfolded crystallin proteins. In this scenario, chaperone pool depletion would result in lens opacification. Here we analyze lenses from different mouse strains that develop early-onset cataract due to point mutations in α-, β-, or γ-crystallin proteins. We find that these mutant crystallins are unstable in vitro; in the lens, their levels are substantially reduced, and they do not accumulate in the water-insoluble fraction. Instead, all the other crystallin proteins, including the α-crystallins, are found to precipitate. The changes in protein composition and spatial organization of the crystallins observed in the mutant lenses suggest that the imbalance in the lenticular proteome and altered crystallin interactions are the bases for cataract formation, rather than the aggregation propensity of the mutant crystallins.
AU  - Schmid, P.W.N.*
AU  - Lim, N.C.H.*
AU  - Peters, C.*
AU  - Back, K.C.*
AU  - Bourgeois, B.*
AU  - Pirolt, F.*
AU  - Richter, B.*
AU  - Peschek, J.*
AU  - Puk, O.
AU  - Amarie, O.V.
AU  - Dalke, C.
AU  - Haslbeck, M.*
AU  - Weinkauf, S.*
AU  - Madl, T.*
AU  - Graw, J.
AU  - Buchner, J.*
C1  - 61105
C2  - 49678
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 143–151
TI  - Imbalances in the eye lens proteome are linked to cataract formation.
JO  - Nat. Struct. Mol. Biol.
VL  - 28
PB  - Nature Research
PY  - 2021
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - G-protein-coupled receptors (GPCRs) are the largest superfamily of transmembrane proteins and the targets of over 30% of currently marketed pharmaceuticals. Although several structures have been solved for GPCR-G protein complexes, few are in a lipid membrane environment. Here, we report cryo-EM structures of complexes of neurotensin, neurotensin receptor 1 and Gαi1β1γ1 in two conformational states, resolved to resolutions of 4.1 and 4.2 Å. The structures, determined in a lipid bilayer without any stabilizing antibodies or nanobodies, reveal an extended network of protein-protein interactions at the GPCR-G protein interface as compared to structures obtained in detergent micelles. The findings show that the lipid membrane modulates the structure and dynamics of complex formation and provide a molecular explanation for the stronger interaction between GPCRs and G proteins in lipid bilayers. We propose an allosteric mechanism for GDP release, providing new insights into the activation of G proteins for downstream signaling.
AU  - Zhang, M.*
AU  - Gui, M.*
AU  - Wang, Z.F.*
AU  - Gorgulla, C.*
AU  - Yu, J.J.*
AU  - Wu, H.*
AU  - Sun, Z.J.*
AU  - Klenk, C.*
AU  - Merklinger, L.*
AU  - Morstein, L.*
AU  - Hagn, F.
AU  - Plückthun, A.*
AU  - Brown, A.*
AU  - Nasr, M.L.*
AU  - Wagner, G.*
C1  - 61474
C2  - 50279
CY  - Heidelberger Platz 3, Berlin, 14197, Germany
SP  - 258-267
TI  - Cryo-EM structure of an activated GPCR-G protein complex in lipid nanodiscs.
JO  - Nat. Struct. Mol. Biol.
VL  - 28
IS  - 3
PB  - Nature Research
PY  - 2021
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - In the version of this article initially published online, in Fig. 6d, the third and fourth bars were incorrectly labeled “DMSO + cytochrome D” and “MLN4924 + cytochrome D,” respectively. They should have been labeled “DMSO + cytochalasin D” and “MLN4924 + cytochalasin D,” respectively. The errors have been corrected in the print, PDF and HTML versions of the article.
AU  - Vogl, A.M.*
AU  - Phu, L.*
AU  - Becerra, R.*
AU  - Giusti, S.A.*
AU  - Verschueren, E.*
AU  - Hinkle, T.B.*
AU  - Bordenave, M.D.*
AU  - Adrian, M.*
AU  - Heidersbach, A.*
AU  - Yankilevich, P.*
AU  - Stefani, F.D.*
AU  - Wurst, W.
AU  - Hoogenraad, C.C.*
AU  - Kirkpatrick, D.S.*
AU  - Refojo, D.*
AU  - Sheng, M.*
C1  - 58487
C2  - 48143
TI  - Publisher Correction: Global site-specific neddylation profiling reveals that NEDDylated cofilin regulates actin dynamics (Nature Structural & Molecular Biology, (2020), 27, 2, (210-220), 10.1038/s41594-019-0370-3).
JO  - Nat. Struct. Mol. Biol.
PY  - 2020
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Neddylation is the post-translational protein modification most closely related to ubiquitination. Whereas the ubiquitin-like protein NEDD8 is well studied for its role in activating cullin−RING E3 ubiquitin ligases, little is known about other substrates. We developed serial NEDD8-ubiquitin substrate profiling (sNUSP), a method that employs NEDD8 R74K knock-in HEK293 cells, allowing discrimination of endogenous NEDD8- and ubiquitin-modification sites by MS after Lys-C digestion and K-εGG-peptide enrichment. Using sNUSP, we identified 607 neddylation sites dynamically regulated by the neddylation inhibitor MLN4924 and the de-neddylating enzyme NEDP1, implying that many non-cullin proteins are neddylated. Among the candidates, we characterized lysine 112 of the actin regulator cofilin as a novel neddylation event. Global inhibition of neddylation in developing neurons leads to cytoskeletal defects, altered actin dynamics and neurite growth impairments, whereas site-specific neddylation of cofilin at K112 regulates neurite outgrowth, suggesting that cofilin neddylation contributes to the regulation of neuronal actin organization.
AU  - Vogl, A.M.*
AU  - Phu, L.*
AU  - Becerra, R.*
AU  - Giusti, S.A.*
AU  - Verschueren, E.*
AU  - Hinkle, T.B.*
AU  - Bordenave, M.D.*
AU  - Adrian, M.*
AU  - Heidersbach, A.*
AU  - Yankilevich, P.*
AU  - Stefani, F.D.*
AU  - Wurst, W.
AU  - Hoogenraad, C.C.*
AU  - Kirkpatrick, D.S.*
AU  - Refojo, D.*
AU  - Sheng, M.*
C1  - 58793
C2  - 48329
SP  - 210-220
TI  - Global site-specific neddylation profiling reveals that NEDDylated cofilin regulates actin dynamics.
JO  - Nat. Struct. Mol. Biol.
VL  - 27
IS  - 2
PY  - 2020
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Polycomb repressive complex 2 (PRC2) maintains repression of cell-type-specific genes but also associates with genes ectopically in cancer. While it is currently unknown how PRC2 is removed from genes, such knowledge would be useful for the targeted reversal of deleterious PRC2 recruitment events. Here, we show that G-tract RNA specifically removes PRC2 from genes in human and mouse cells. PRC2 preferentially binds G tracts within nascent precursor mRNA (pre-mRNA), especially within predicted G-quadruplex structures. G-quadruplex RNA evicts the PRC2 catalytic core from the substrate nucleosome. In cells, PRC2 transfers from chromatin to pre-mRNA upon gene activation, and chromatin-associated G-tract RNA removes PRC2, leading to H3K27me3 depletion from genes. Targeting G-tract RNA to the tumor suppressor gene CDKN2A in malignant rhabdoid tumor cells reactivates the gene and induces senescence. These data support a model in which pre-mRNA evicts PRC2 during gene activation and provides the means to selectively remove PRC2 from specific genes.
AU  - Beltran, M.*
AU  - Tavares, M.*
AU  - Justin, N.*
AU  - Khandelwal, G.*
AU  - Ambrose, J.*
AU  - Foster, B.
AU  - Worlock, K.B.*
AU  - Kunzelmann, S.*
AU  - Herrero, J.*
AU  - Bartke, T.
AU  - Gamblin, S.J.*
AU  - Wilson, J.R.*
AU  - Jenner, R.G.*
C1  - 57114
C2  - 47541
CY  - 75 Varick St, 9th Flr, New York, Ny 10013-1917 Usa
SP  - 899-909
TI  - G-tract RNA removes Polycomb repressive complex 2 from genes.
JO  - Nat. Struct. Mol. Biol.
VL  - 26
IS  - 10
PB  - Nature Publishing Group
PY  - 2019
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - In the version of this article initially published, Fig. 4 included some errors. In Fig. 4c, the color for the left bar in each set of three bars (green) was incorrect; the correct color is orange (H2AK119ub, as in key). In Fig. 4d, top row, the downward error bars for H3K27me3 in the top middle plot (Fgf11 B) were incorrect; the correct s.d. in the negative direction is smaller for each. In Fig. 4d, bottom row, the far left downward error bar for HA-dCas9 in the left plot (Fgf11 A) was incorrect; the correct s.d. in the negative direction is larger. The errors have been corrected in the HTML and PDF versions of the article. (Figure presented.).
AU  - Beltran, M.*
AU  - Tavares, M.*
AU  - Justin, N.*
AU  - Khandelwal, G.*
AU  - Ambrose, J.*
AU  - Foster, B.
AU  - Worlock, K.B.*
AU  - Tvardovskiy, A.
AU  - Kunzelmann, S.*
AU  - Herrero, J.*
AU  - Bartke, T.
AU  - Gamblin, S.J.*
AU  - Wilson, J.R.*
AU  - Jenner, R.G.*
C1  - 57359
C2  - 47722
TI  - Author Correction: G-tract RNA removes Polycomb repressive complex 2 from genes (Nature Structural & Molecular Biology, (2019), 26, 10, (899-909), 10.1038/s41594-019-0293-z).
JO  - Nat. Struct. Mol. Biol.
PY  - 2019
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - The small heat shock protein αA-crystallin is a molecular chaperone important for the optical properties of the vertebrate eye lens. It forms heterogeneous oligomeric ensembles. We determined the structures of human αA-crystallin oligomers by combining cryo-electron microscopy, cross-linking/mass spectrometry, NMR spectroscopy and molecular modeling. The different oligomers can be interconverted by the addition or subtraction of tetramers, leading to mainly 12-, 16- and 20-meric assemblies in which interactions between N-terminal regions are important. Cross-dimer domain-swapping of the C-terminal region is a determinant of αA-crystallin heterogeneity. Human αA-crystallin contains two cysteines, which can form an intramolecular disulfide in vivo. Oxidation in vitro requires conformational changes and oligomer dissociation. The oxidized oligomers, which are larger than reduced αA-crystallin and destabilized against unfolding, are active chaperones and can transfer the disulfide to destabilized substrate proteins. The insight into the structure and function of αA-crystallin provides a basis for understanding its role in the eye lens.
AU  - Kaiser, C.J.O.*
AU  - Peters, C.*
AU  - Schmid, P.W.N.*
AU  - Stavropoulou, M.
AU  - Zou, J.*
AU  - Dahiya, V.*
AU  - Mymrikov, E.V.*
AU  - Rockel, B.*
AU  - Asami, S.
AU  - Haslbeck, M.*
AU  - Rappsilber, J.*
AU  - Reif, B.
AU  - Zacharias, M.*
AU  - Buchner, J.*
AU  - Weinkauf, S.*
C1  - 57498
C2  - 47814
SP  - 1141-1150
TI  - The structure and oxidation of the eye lens chaperone αA-crystallin.
JO  - Nat. Struct. Mol. Biol.
VL  - 26
IS  - 12
PY  - 2019
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Histone 3 K4 trimethylation (depositing H3K4me3 marks) is typically associated with active promoters yet paradoxically occurs at untranscribed domains. Research to delineate the mechanisms of targeting H3K4 methyltransferases is ongoing. The oocyte provides an attractive system to investigate these mechanisms, because extensive H3K4me3 acquisition occurs in nondividing cells. We developed low-input chromatin immunoprecipitation to interrogate H3K4me3, H3K27ac and H3K27me3 marks throughout oogenesis. In nongrowing oocytes, H3K4me3 was restricted to active promoters, but as oogenesis progressed, H3K4me3 accumulated in a transcription-independent manner and was targeted to intergenic regions, putative enhancers and silent H3K27me3-marked promoters. Ablation of the H3K4 methyltransferase gene Mll2 resulted in loss of transcription-independent H3K4 trimethylation but had limited effects on transcription-coupled H3K4 trimethylation or gene expression. Deletion of Dnmt3a and Dnmt3b showed that DNA methylation protects regions from acquiring H3K4me3. Our findings reveal two independent mechanisms of targeting H3K4me3 to genomic elements, with MLL2 recruited to unmethylated CpG-rich regions independently of transcription.
AU  - Hanna, C.W.*
AU  - Taudt, A.
AU  - Huang, J.*
AU  - Gahurova, L.*
AU  - Kranz, A.*
AU  - Andrews, S.*
AU  - Dean, W.*
AU  - Stewart, A.F.*
AU  - Colomé-Tatché, M.
AU  - Kelsey, G.*
C1  - 52956
C2  - 44394
CY  - New York
SP  - 73-82
TI  - MLL2 conveys transcription-independent H3K4 trimethylation in oocytes.
JO  - Nat. Struct. Mol. Biol.
VL  - 25
IS  - 1
PB  - Nature Publishing Group
PY  - 2018
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - mRNA localization is an essential mechanism of gene regulation and is required for processes such as stem-cell division, embryogenesis and neuronal plasticity. It is not known which features in the cis-acting mRNA localization elements (LEs) are specifically recognized by motor-containing transport complexes. To the best of our knowledge, no high-resolution structure is available for any LE in complex with its cognate protein complex. Using X-ray crystallography and complementary techniques, we carried out a detailed assessment of an LE of the ASH1 mRNA from yeast, its complex with its shuttling RNA-binding protein She2p, and its highly specific, cytoplasmic complex with She3p. Although the RNA alone formed a flexible stem loop, She2p binding induced marked conformational changes. However, only joining by the unstructured She3p resulted in specific RNA recognition. The notable RNA rearrangements and joint action of a globular and an unfolded RNA-binding protein offer unprecedented insights into the step-wise maturation of an mRNA-transport complex.
AU  - Edelmann, F.
AU  - Schlundt, A.*
AU  - Heym, R.G.
AU  - Jenner, A.*
AU  - Niedner-Boblenz, A.*
AU  - Syed, M.I.*
AU  - Paillart, J.C.*
AU  - Stehle, R.*
AU  - Janowski, R.
AU  - Sattler, M.
AU  - Jansen, R.P.*
AU  - Niessing, D.
C1  - 50408
C2  - 42388
CY  - New York
SP  - 152-161
TI  - Molecular architecture and dynamics of ASH1 mRNA recognition by its mRNA-transport complex.
JO  - Nat. Struct. Mol. Biol.
VL  - 24
IS  - 2
PB  - Nature Publishing Group
PY  - 2017
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Histones are highly covalently modified, but the functions of many of these modifications remain unknown. In particular, it is unclear how histone marks are coupled to cellular metabolism and how this coupling affects chromatin architecture. We identified histone H3 Lys14 (H3K14) as a site of propionylation and butyrylation in vivo and carried out the first systematic characterization of histone propionylation. We found that H3K14pr and H3K14bu are deposited by histone acetyltransferases, are preferentially enriched at promoters of active genes and are recognized by acylation-state-specific reader proteins. In agreement with these findings, propionyl-CoA was able to stimulate transcription in an in vitro transcription system. Notably, genome-wide H3 acylation profiles were redefined following changes to the metabolic state, and deletion of the metabolic enzyme propionyl-CoA carboxylase altered global histone propionylation levels. We propose that histone propionylation, acetylation and butyrylation may act in combination to promote high transcriptional output and to couple cellular metabolism with chromatin structure and function.
AU  - Kebede, A.F.*
AU  - Nieborak, A.
AU  - Shahidian, L.Z.
AU  - Le Gras, S.*
AU  - Richter, F.M.*
AU  - Gomez, D.A.
AU  - Baltissen, M.P.*
AU  - Meszaros, G.*
AU  - Magliarelli, H.F.*
AU  - Taudt, A.
AU  - Margueron, R.*
AU  - Colomé-Tatché, M.
AU  - Ricci, R.*
AU  - Daujat, S.*
AU  - Vermeulen, M.*
AU  - Mittler, G.*
AU  - Schneider, R.
C1  - 52181
C2  - 43826
CY  - New York
SP  - 1048–1056
TI  - Histone propionylation is a mark of active chromatin.
JO  - Nat. Struct. Mol. Biol.
VL  - 24
IS  - 12
PB  - Nature Publishing Group
PY  - 2017
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Nature Structural & Molecular Biology | Article Print Share/bookmark       MacroH2A1.1 regulates mitochondrial respiration by limiting nuclear NAD+ consumption Melanija Posavec Marjanović, Sarah Hurtado-Bagès, Maximilian Lassi, Vanesa Valero, Roberto Malinverni, Hélène Delage, Miriam Navarro, David Corujo, Iva Guberovic, Julien Douet, Pau Gama-Perez, Pablo M Garcia-Roves, Ivan Ahel, Andreas G Ladurner, Oscar Yanes, Philippe Bouvet, Mònica Suelves, Raffaele Teperino, J Andrew Pospisilik & Marcus Buschbeck Affiliations Contributions Corresponding authors Nature Structural & Molecular Biology (2017) doi:10.1038/nsmb.3481 Received 07 March 2017 Accepted 13 September 2017 Published online 09 October 2017 Article tools PDF Citation Rights & permissions Article metrics Abstract Abstract• Introduction• Results• Discussion• Methods• Additional information• Accession codes• References• Acknowledgments• Author information• Supplementary information Histone variants are structural components of eukaryotic chromatin that can replace replication-coupled histones in the nucleosome. The histone variant macroH2A1.1 contains a macrodomain capable of binding NAD+-derived metabolites. Here we report that macroH2A1.1 is rapidly induced during myogenic differentiation through a switch in alternative splicing, and that myotubes that lack macroH2A1.1 have a defect in mitochondrial respiratory capacity. We found that the metabolite-binding macrodomain was essential for sustained optimal mitochondrial function but dispensable for gene regulation. Through direct binding, macroH2A1.1 inhibits basal poly-ADP ribose polymerase 1 (PARP-1) activity and thus reduces nuclear NAD+ consumption. The resultant accumulation of the NAD+ precursor NMN allows for maintenance of mitochondrial NAD+ pools that are critical for respiration. Our data indicate that macroH2A1.1-containing chromatin regulates mitochondrial respiration by limiting nuclear NAD+ consumption and establishing a buffer of NAD+ precursors in differentiated cells.
AU  - Marjanović, M.P.*
AU  - Hurtado-Bagès, S.*
AU  - Lassi, M.
AU  - Valero, V.*
AU  - Malinverni, R.*
AU  - Delage, H.*
AU  - Navarro, M.*
AU  - Corujo, D.*
AU  - Guberovic, I.*
AU  - Douet, J.*
AU  - Gama-Perez, P.*
AU  - Garcia-Roves, P.M.*
AU  - Ahel, I.*
AU  - Ladurner, A.G.*
AU  - Yanes, O.*
AU  - Bouvet, P.*
AU  - Suelves, M.*
AU  - Teperino, R.
AU  - Pospisilik, J.A.*
AU  - Buschbeck, M.*
C1  - 52066
C2  - 43694
CY  - New York
SP  - 902-910
TI  - MacroH2A1.1 regulates mitochondrial respiration by limiting nucleas NAD+ consumption.
JO  - Nat. Struct. Mol. Biol.
VL  - 24
IS  - 11
PB  - Nature Publishing Group
PY  - 2017
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Signaling cascades depend on scaffold proteins that regulate the assembly of multiprotein complexes. Missense mutations in scaffold proteins are frequent in human cancer, but their relevance and mode of action are poorly understood. Here we show that cancer point mutations in the scaffold protein Axin derail Wnt signaling and promote tumor growth in vivo through a gain-of-function mechanism. The effect is conserved for both the human and Drosophila proteins. Mutated Axin forms nonamyloid nanometer-scale aggregates decorated with disordered tentacles, which 'rewire' the Axin interactome. Importantly, the tumor-suppressor activity of both the human and Drosophila Axin cancer mutants is rescued by preventing aggregation of a single nonconserved segment. Our findings establish a new paradigm for misregulation of signaling in cancer and show that targeting aggregation-prone stretches in mutated scaffolds holds attractive potential for cancer treatment.
AU  - Anvarian, Z.*
AU  - Nojima, H.*
AU  - van Kappel, E.C.*
AU  - Madl, T.
AU  - Spit, M.*
AU  - Viertler, M.
AU  - Jordens, I.*
AU  - Low, T.Y.*
AU  - van Scherpenzeel, R.C.*
AU  - Kuper, I.*
AU  - Richter, K.*
AU  - Heck, A.J.*
AU  - Boelens, R.*
AU  - Vincent, J.P.*
AU  - Rüdiger, S.G.*
AU  - Maurice, M.M.*
C1  - 48105
C2  - 39909
CY  - New York
SP  - 324-332
TI  - Axin cancer mutants form nanoaggregates to rewire the Wnt signaling network.
JO  - Nat. Struct. Mol. Biol.
VL  - 23
IS  - 4
PB  - Nature Publishing Group
PY  - 2016
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Hsp90 couples ATP hydrolysis to large conformational changes essential for activation of client proteins. The structural transitions involve dimerization of the N-terminal domains and formation of 'closed states' involving the N-terminal and middle domains. Here, we used Hsp90 mutants that modulate ATPase activity and biological function as probes to address the importance of conformational cycling for Hsp90 activity. We found no correlation between the speed of ATP turnover and the in vivo activity of Hsp90: some mutants with almost normal ATPase activity were lethal, and some mutants with lower or undetectable ATPase activity were viable. Our analysis showed that it is crucial for Hsp90 to attain and spend time in certain conformational states: a certain dwell time in open states is required for optimal processing of client proteins, whereas a prolonged population of closed states has negative effects. Thus, the timing of conformational transitions is crucial for Hsp90 function and not cycle speed.
AU  - Zierer, B.K.*
AU  - Rübbelke, M.
AU  - Tippel, F.*
AU  - Madl, T.
AU  - Schopf, F.H.*
AU  - Rutz, D.A.*
AU  - Richter, K.*
AU  - Sattler, M.
AU  - Buchner, J.*
C1  - 49976
C2  - 41957
CY  - New York
SP  - 1020-1028
TI  - Importance of cycle timing for the function of the molecular chaperone Hsp90.
JO  - Nat. Struct. Mol. Biol.
VL  - 23
IS  - 11
PB  - Nature Publishing Group
PY  - 2016
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Small heat-shock proteins, including αB-crystallin (αB), play an important part in protein homeostasis, because their ATP-independent chaperone activity inhibits uncontrolled protein aggregation. Mechanistic details of human αB, particularly in its client-bound state, have been elusive so far, owing to the high molecular weight and the heterogeneity of these complexes. Here we provide structural insights into this highly dynamic assembly and show, by using state-of-the-art NMR spectroscopy, that the αB complex is assembled from asymmetric building blocks. Interaction studies demonstrated that the fibril-forming Alzheimer's disease Aβ1-40 peptide preferentially binds to a hydrophobic edge of the central β-sandwich of αB. In contrast, the amorphously aggregating client lysozyme is captured by the partially disordered N-terminal domain of αB. We suggest that αB uses its inherent structural plasticity to expose distinct binding interfaces and thus interact with a wide range of structurally variable clients.
AU  - Mainz, A.*
AU  - Peschek, J.*
AU  - Stavropoulou, M.*
AU  - Back, K.C.*
AU  - Bardiaux, B.*
AU  - Asami, S.*
AU  - Prade, E.*
AU  - Peters, C.*
AU  - Weinkauf, S.*
AU  - Buchner, J.*
AU  - Reif, B.
C1  - 47106
C2  - 39167
SP  - 898-905
TI  - The  chaperone αB-crystallin uses different interfaces to capture an amorphous and an amyloid client
JO  - Nat. Struct. Mol. Biol.
VL  - 22
IS  - 11
PY  - 2015
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Roquin function in T cells is essential for the prevention of autoimmune disease. Roquin interacts with the 3′ untranslated regions (UTRs) of co-stimulatory receptors and controls T-cell activation and differentiation. Here we show that the N-terminal ROQ domain from mouse roquin adopts an extended winged-helix (WH) fold, which is sufficient for binding to the constitutive decay element (CDE) in the Tnf 3′ UTR. The crystal structure of the ROQ domain in complex with a prototypical CDE RNA stem-loop reveals tight recognition of the RNA stem and its triloop. Surprisingly, roquin uses mainly non-sequence-specific contacts to the RNA, thus suggesting a relaxed CDE consensus and implicating a broader spectrum of target mRNAs than previously anticipated. Consistently with this, NMR and binding experiments with CDE-like stem-loops together with cell-based assays confirm roquin-dependent regulation of relaxed CDE consensus motifs in natural 3′ UTRs.
AU  - Schlundt, A.
AU  - Heinz, G.A.
AU  - Janowski, R.
AU  - Geerlof, A.
AU  - Stehle, R.*
AU  - Heissmeyer, V.
AU  - Niessing, D.
AU  - Sattler, M.
C1  - 31758
C2  - 34712
CY  - New York
SP  - 671-678
TI  - Structural basis for RNA recognition in roquin-mediated post-transcriptional gene regulation.
JO  - Nat. Struct. Mol. Biol.
VL  - 21
IS  - 8
PB  - Nature Publishing Group
PY  - 2014
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - The exoRNase Eri1 inhibits RNA interference and trims the 5.8S rRNA 3' end. It also binds to the stem-loop of histone mRNAs, but the functional importance of this interaction remains elusive. Histone mRNAs are normally degraded at the end of S phase or after pharmacological inhibition of replication. Both processes are impaired in Eri1-deficient mouse cells, which instead accumulate oligouridylated histone mRNAs. Eri1 trims the mature histone mRNAs by two unpaired nucleotides at the 3' end but stalls close to the double-stranded stem. Upon oligouridylation of the histone mRNA, the Lsm1-7 heteroheptamer recognizes the oligo(U) tail and interacts with Eri1, whose catalytic activity is then able to degrade the stem-loop in a stepwise manner. These data demonstrate how degradation of histone mRNAs is initiated when 3' oligouridylation creates a cis element that enables Eri1 to process the double-stranded stem-loop structure.
AU  - Höfig, K.P.
AU  - Rath, N.
AU  - Heinz, G.A.
AU  - Wolf, C.
AU  - Dameris, J.
AU  - Schepers, A.
AU  - Kremmer, E.
AU  - Ansel, K.M.*
AU  - Heissmeyer, V.
C1  - 11573
C2  - 30695
SP  - 73-81
TI  - Eri1 degrades the stem-loop of oligouridylated histone mRNAs to induce replication-dependent decay.
JO  - Nat. Struct. Mol. Biol.
VL  - 20
IS  - 1
PB  - Nature Publishing Group
PY  - 2013
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Chromodomains typically recruit protein complexes to chromatin and read the epigenetic histone code by recognizing lysine methylation in histone tails. We report the crystal structure of the chloroplast signal recognition particle (cpSRP) core from Arabidopsis thaliana, with the cpSRP54 tail comprising an arginine-rich motif bound to the second chromodomain of cpSRP43. A twinned aromatic cage reads out two neighboring nonmethylated arginines and adapts chromodomains to a non-nuclear function in post-translational targeting.
AU  - Holdermann, I.*
AU  - Meyer, N.H.
AU  - Round, A.*
AU  - Wild, K.*
AU  - Sattler, M.
AU  - Sinning, I.*
C1  - 7224
C2  - 29568
SP  - 260-263
TI  - Chromodomains read the arginine code of post-translational targeting.
JO  - Nat. Struct. Mol. Biol.
VL  - 19
IS  - 2
PB  - Nature Publishing Group
PY  - 2012
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Several lines of recent evidence support a role for chromatin in splicing regulation. Here, we show that splicing can also contribute to histone modification, which implies bidirectional communication between epigenetic mechanisms and RNA processing. Genome-wide analysis of histone methylation in human cell lines and mouse primary T cells reveals that intron-containing genes are preferentially marked with histone H3 Lys36 trimethylation (H3K36me3) relative to intronless genes. In intron-containing genes, H3K36me3 marking is proportional to transcriptional activity, whereas in intronless genes, H3K36me3 is always detected at much lower levels. Furthermore, splicing inhibition impairs recruitment of H3K36 methyltransferase HYPB (also known as Setd2) and reduces H3K36me3, whereas splicing activation has the opposite effect. Moreover, the increase of H3K36me3 correlates with the length of the first intron, consistent with the view that splicing enhances H3 methylation. We propose that splicing is mechanistically coupled to recruitment of HYPB/Setd2 to elongating RNA polymerase II.
AU  - de Almeida, S.F.*
AU  - Grosso, A.R.*
AU  - Koch, F.*
AU  - Fenouil, R.*
AU  - Carvalho, S.*
AU  - Andrade, J.*
AU  - Levezinho, H.*
AU  - Gut, M.*
AU  - Eick, D.
AU  - Gut, I.*
AU  - Andrau, J.C.*
AU  - Ferrier, P.*
AU  - Carmo-Fonseca, M.*
C1  - 3750
C2  - 28942
SP  - 977-984
TI  - Splicing enhances recruitment of methyltransferase HYPB/Setd2 and methylation of histone H3 Lys36.
JO  - Nat. Struct. Mol. Biol.
VL  - 18
IS  - 9
PB  - Nature Publ. Group
PY  - 2011
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Recent work has shown that RNA polymerase (Pol) II can be recruited to and transcribe distal regulatory regions. Here we analyzed transcription initiation and elongation through genome-wide localization of Pol II, general transcription factors (GTFs) and active chromatin in developing T cells. We show that Pol II and GTFs are recruited to known T cell-specific enhancers. We extend this observation to many new putative enhancers, a majority of which can be transcribed with or without polyadenylation. Importantly, we also identify genomic features called transcriptional initiation platforms (TIPs) that are characterized by large areas of Pol II and GTF recruitment at promoters, intergenic and intragenic regions. TIPs show variable widths (0.4-10 kb) and correlate with high CpG content and increased tissue specificity at promoters. Finally, we also report differential recruitment of TFIID and other GTFs at promoters and enhancers. Overall, we propose that TIPs represent important new regulatory hallmarks of the genome.
AU  - Koch, F.*
AU  - Fenouil, R.*
AU  - Gut, M.*
AU  - Cauchy, P.*
AU  - Albert, T.K.*
AU  - Zacarias-Cabeza, J.*
AU  - Spicuglia, S.*
AU  - de la Chapelle, A.L.*
AU  - Heidemann, M.
AU  - Hintermair, C.
AU  - Eick, D.
AU  - Gut, I.*
AU  - Ferrier, P.*
AU  - Andrau, J.C.*
C1  - 6588
C2  - 28950
SP  - 956-963
TI  - Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters.
JO  - Nat. Struct. Mol. Biol.
VL  - 18
IS  - 8
PB  - Nature Publ. Group
PY  - 2011
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Arginine dimethylation plays critical roles in the assembly of ribonucleoprotein complexes in pre-mRNA splicing and piRNA pathways. We report solution structures of SMN and SPF30 Tudor domains bound to symmetric and asymmetric dimethylated arginine (DMA) that is inherent in the RNP complexes. An aromatic cage in the Tudor domain mediates dimethylarginine recognition by electrostatic stabilization through cation-π interactions. Distinct from extended Tudor domains, dimethylarginine binding by the SMN and SPF30 Tudor domains is independent of proximal residues in the ligand. Yet, enhanced micromolar affinities are obtained by external cooperativity when multiple methylation marks are presented in arginine- and glycine-rich peptide ligands. A hydrogen bond network in the SMN Tudor domain, including Glu134 and a tyrosine hydroxyl of the aromatic cage, enhances cation-π interactions and is impaired by a mutation causing an E134K substitution associated with spinal muscular atrophy. Our structural analysis enables the design of an optimized binding pocket and the prediction of DMA binding properties of Tudor domains.
AU  - Tripsianes, K.
AU  - Madl, T.
AU  - Machyna, M.*
AU  - Fessas, D.*
AU  - Englbrecht, C.*
AU  - Fischer, U.*
AU  - Neugebauer, K.M.*
AU  - Sattler, M.
C1  - 6823
C2  - 29317
SP  - 1414-1420
TI  - Structural basis for dimethylarginine recognition by the Tudor domains of human SMN and SPF30 proteins.
JO  - Nat. Struct. Mol. Biol.
VL  - 18
IS  - 12
PB  - Nature Publishing Group
PY  - 2011
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Eukaryotic transcription is regulated by interactions between gene-specific activators and the coactivator complex Mediator. Here we report the NMR structure of the Mediator subunit Med25 (also called Arc92) activator interaction domain (ACID) and analyze the structural and functional interaction of ACID with the archetypical acidic transcription activator VP16. Unlike other known activator targets, ACID forms a seven-stranded β-barrel framed by three helices. The VP16 subdomains H1 and H2 bind to opposite faces of ACID and cooperate during promoter-dependent activated transcription in a in vitro system. The activator-binding ACID faces are functionally required and conserved among higher eukaryotes. Comparison with published activator structures reveals that the VP16 activation domain uses distinct interaction modes to adapt to unrelated target surfaces and folds that evolved for activator binding.
AU  - Vojnic, E.*
AU  - Mourao, A.
AU  - Seizl, M.*
AU  - Simon, B.*
AU  - Wenzeck, L.*
AU  - Larivière, L.*
AU  - Baumli, S.*
AU  - Baumgart, K.*
AU  - Meisterernst, M.*
AU  - Sattler, M.
AU  - Cramer, P.*
C1  - 6547
C2  - 28859
SP  - 404-410
TI  - Structure and VP16 binding of the Mediator Med25 activator interaction domain.
JO  - Nat. Struct. Mol. Biol.
VL  - 18
IS  - 4
PB  - Nature Publ. Group
PY  - 2011
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs. These NESs differ markedly in the spacing of their key hydrophobic (Φ) residues, yet CRM1 recognizes them with the same rigid set of five Φ pockets. The different Φ spacings are compensated for by different conformations of the bound NESs: in the case of PKI, an α-helical conformation, and in the case of Rev, an extended conformation with a critical proline docking into a Φ pocket. NMR analyses of CRM1-bound and CRM1-free PKI NES suggest that CRM1 selects NES conformers that pre-exist in solution. Our data lead to a new structure-based NES consensus, and explain why NESs differ in their affinities for CRM1 and why supraphysiological NESs bind the exportin so tightly.
AU  - Güttler, T.*
AU  - Madl, T.
AU  - Neumann, P.*
AU  - Deichsel, D.*
AU  - Corsini, L.
AU  - Monecke, T.*
AU  - Ficner, R.*
AU  - Sattler, M.
AU  - Görlich, D.*
C1  - 5662
C2  - 27931
SP  - 1367-1376
TI  - NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1.
JO  - Nat. Struct. Mol. Biol.
VL  - 17
IS  - 11
PB  - Nature Publ. Group
PY  - 2010
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Sequential modifications of the RNA polymerase II (Pol II) C-terminal domain (CTD) coordinate the stage-specific association and release of cellular machines during transcription. Here we examine the genome-wide distributions of the 'early' (phospho-Ser5 (Ser5-P)), 'mid' (Ser7-P) and 'late' (Ser2-P) CTD marks. We identify gene class-specific patterns and find widespread co-occurrence of the CTD marks. Contrary to its role in 3'-processing of noncoding RNA, the Ser7-P marks are placed early and retained until transcription termination at all Pol II-dependent genes. Chemical-genomic analysis reveals that the promoter-distal Ser7-P marks are not remnants of early phosphorylation but are placed anew by the CTD kinase Bur1. Consistent with the ability of Bur1 to facilitate transcription elongation and suppress cryptic transcription, high levels of Ser7-P are observed at highly transcribed genes. We propose that Ser7-P could facilitate elongation and suppress cryptic transcription.
AU  - Tietjen, J.R.*
AU  - Zhang, D.W.*
AU  - Rodriguez-Molina, J.B.*
AU  - White, B.E.*
AU  - Akhtar, M.S.*
AU  - Heidemann, M.
AU  - Li, X.*
AU  - Chapman, R.D.
AU  - Shokat, K.*
AU  - Keles, S.*
AU  - Eick, D.
AU  - Ansari, A.Z.*
C1  - 5907
C2  - 27437
SP  - 1154-1161
TI  - Chemical-genomic dissection of the CTD code.
JO  - Nat. Struct. Mol. Biol.
VL  - 17
IS  - 9
PB  - Nature Publ. Group
PY  - 2010
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Eri1 is a 3'-to-5' exoribonuclease conserved from fission yeast to humans. Here we show that Eri1 associates with ribosomes and ribosomal RNA (rRNA). Ribosomes from Eri1-deficient mice contain 5.8S rRNA that is aberrantly extended at its 3' end, and Eri1, but not a catalytically inactive mutant, converts this abnormal 5.8S rRNA to the wild-type form in vitro and in cells. In human and murine cells, Eri1 localizes to the cytoplasm and nucleus, with enrichment in the nucleolus, the site of preribosome biogenesis. RNA binding residues in the Eri1 SAP and linker domains promote stable association with rRNA and thereby facilitate 5.8S rRNA 3' end processing. Taken together, our findings indicate that Eri1 catalyzes the final trimming step in 5.8S rRNA processing, functionally and spatially connecting this regulator of RNAi with the basal translation machinery.
AU  - Ansel, K.M.*
AU  - Pastor, W.A.*
AU  - Rath, N.
AU  - Lapan, A.D.*
AU  - Glasmacher, E.
AU  - Wolf, C.
AU  - Smith, L.C.*
AU  - Papadopoulou, N.
AU  - Lamperti, E.D.*
AU  - Tahiliani, M.*
AU  - Ellwart, J.W.
AU  - Shi, Y.*
AU  - Kremmer, E.
AU  - Rao, A.*
AU  - Heissmeyer, V.
C1  - 782
C2  - 25445
SP  - 523-530
TI  - Mouse Eri1 interacts with the ribosome and catalyzes 5.8S rRNA processing.
JO  - Nat. Struct. Mol. Biol.
VL  - 15
IS  - 5
PB  - Nature Publ. Comp.
PY  - 2008
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - Histone lysine methylation has a central role in transcriptional regulation and has recently been linked to DNA damage repair. Now it has been shown that the DNA damage repair factor 53BP1 is recruited to DNA double-strand breaks by its tandem tudor domain, which specifically recognizes histone H4 dimethylated at lysine 20.
AU  - Corsini, L.*
AU  - Sattler, M.
C1  - 596
C2  - 24821
SP  - 98-99
TI  - Tudor hooks up with DNA repair.
JO  - Nat. Struct. Mol. Biol.
VL  - 14
IS  - 2
PB  - Nature Publ. Group
PY  - 2007
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - The U2AF-homology motif (UHM) mediates protein-protein interactions between factors involved in constitutive RNA splicing. Here we report that the splicing factor SPF45 regulates alternative splicing of the apoptosis regulatory gene FAS (also called CD95). The SPF45 UHM is necessary for this activity and binds UHM-ligand motifs (ULMs) present in the 3' splice site-recognizing factors U2AF65, SF1 and SF3b155. We describe a 2.1-A crystal structure of SPF45-UHM in complex with a ULM peptide from SF3b155. Features distinct from those of previously described UHM-ULM structures allowed the design of mutations in the SPF45 UHM that selectively impair binding to individual ULMs. Splicing assays using the ULM-selective SPF45 variants demonstrate that individual UHM-ULM interactions are required for FAS splicing regulation by SPF45 in vivo. Our data suggest that networks of UHM-ULM interactions are involved in regulating alternative splicing.
AU  - Corsini, L.*
AU  - Bonnal, S.*
AU  - Basquin, J.*
AU  - Hothorn, M.*
AU  - Scheffzek, K.*
AU  - Valcárcel, J.*
AU  - Sattler, M.
C1  - 1878
C2  - 24820
SP  - 620-629
TI  - U2AF-homology motif interactions are required for alternative splicing regulation by SPF45.
JO  - Nat. Struct. Mol. Biol.
VL  - 14
IS  - 7
PB  - Nature Publ. Group
PY  - 2007
SN  - 1545-9993
ER  - 

TY  - JOUR
AB  - The general transcription factors (GTFs) of eukaryotic RNA polymerase II, in a process facilitated by regulatory and accessory factors, target promoters through synergistic interactions with core elements. The specific binding of the TATA box-binding protein (TBP) to the TATA box has led to the assumption that GTFs recognize promoters directly, producing a preinitiation complex at a defined position. Using biochemical analysis as well as biophysical single-pair Förster resonance energy transfer, we now provide evidence that negative cofactor-2 (NC2) induces dynamic conformational changes in the TBP-DNA complex that allow it to escape and return to TATA-binding mode. This can lead to movement of TBP along the DNA away from TATA.
AU  - Schluesche, P.*
AU  - Stelzer, G.
AU  - Piaia, E.
AU  - Lamb, D.C.*
AU  - Meisterernst, M.
C1  - 819
C2  - 24883
SP  - 1196-1201
TI  - NC2 mobilizes TBP on core promoter TATA boxes.
JO  - Nat. Struct. Mol. Biol.
VL  - 14
IS  - 12
PB  - Nature Publ. Group
PY  - 2007
SN  - 1545-9993
ER  -