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Boldt, K.* ; van Reeuwijk, J.* ; Lu, Q.* ; Koutroumpas, K.* ; Nguyen, T.M.* ; Texier, Y. ; van Beersum, S.E.* ; Horn, N.* ; Willer, J.R.* ; Mans, D.A.* ; Dougherty, G.* ; Lamers, I.J.* ; Coene, K.L.* ; Arts, H.H.* ; Betts, M.J.* ; Beyer, T.* ; Bolat, E.* ; Gloeckner, C.J.* ; Haidari, K.* ; Hetterschijt, L.* ; Iaconis, D.* ; Jenkins, D.* ; Klose, F.* ; Knapp, B.* ; Latour, B.* ; Letteboer, S.J.* ; Marcelis, C.L.* ; Mitic, D.* ; Morleo, M.* ; Oud, M.M.* ; Riemersma, M.* ; Rix, S.* ; Terhal, P.A.* ; Toedt, G.* ; van Dam, T.J.* ; de Vrieze, E.* ; Wissinger, Y.* ; Wu, K.M.* ; Apic, G.* ; Beales, P.L.* ; Blacque, O.E.* ; Gibson, T.J.* ; Huynen, M.A.* ; Katsanis, N.* ; Kremer, H.* ; Omran, H.* ; van Wijk, E. ; Wolfrum, U.* ; Kepes, F.* ; Davis, E.E.* ; Franco, B.* ; Giles, R.H.* ; Ueffing, M.* ; Russell, R.B.* ; Roepman, R.*

An organelle-specific protein landscape identifies novel diseases and molecular mechanisms.

Nat. Commun. 7:11491 (2016)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Cellular organelles provide opportunities to relate biological mechanisms to disease. Here we use affinity proteomics, genetics and cell biology to interrogate cilia: poorly understood organelles, where defects cause genetic diseases. Two hundred and seventeen tagged human ciliary proteins create a final landscape of 1,319 proteins, 4,905 interactions and 52 complexes. Reverse tagging, repetition of purifications and statistical analyses, produce a high-resolution network that reveals organelle-specific interactions and complexes not apparent in larger studies, and links vesicle transport, the cytoskeleton, signalling and ubiquitination to ciliary signalling and proteostasis. We observe sub-complexes in exocyst and intraflagellar transport complexes, which we validate biochemically, and by probing structurally predicted, disruptive, genetic variants from ciliary disease patients. The landscape suggests other genetic diseases could be ciliary including 3M syndrome. We show that 3M genes are involved in ciliogenesis, and that patient fibroblasts lack cilia. Overall, this organelle-specific targeting strategy shows considerable promise for Systems Medicine.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Tandem Affinity Purification; Intraflagellar Transport; Statistical-model; Mass-spectrometry; Human Interactome; Network Reveals; Primary Cilia; Complex; Ciliogenesis; Cells
Language english
Publication Year 2016
HGF-reported in Year 2016
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 7, Issue: , Pages: , Article Number: 11491 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Functional Epigenetics (IFE)
POF-Topic(s) 30203 - Molecular Targets and Therapies
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502890-001
PubMed ID 27173435
DOI 10.1038/ncomms11491
WOS ID WOS:000375929800001
Scopus ID 84968718737
Erfassungsdatum 2016-05-25
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