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Langstein-Skora, I.* ; Schmid, A.* ; Huth, F.* ; Shabani, D.* ; Spechtenhauser, L.* ; Likhodeeva, M.* ; Kunert, F.* ; Metzner, F.J.* ; Emenecker, R.J.* ; Richardson, M.O.* ; Aftab, W.* ; Götz, M.J.* ; Payer, S.* ; Pietrantoni, N.* ; Valka, V.* ; Ravichandran, S.K.* ; Bartke, T. ; Karl-Peter, H.* ; Gerland, U.* ; Korber, P.* ; Holehouse, A.S.*

Sequence and chemical specificity define the functional landscape of intrinsically disordered regions.

Nat. Cell Biol. 28, 323-337 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Intrinsically disordered regions (IDRs) pervasively engage in essential molecular functions, yet they are often poorly conserved as assessed by sequence alignment. To explore the seeming paradox of how sequence variability is compatible with persistent function, we examined the functional determinants for a poorly conserved but essential IDR. We show that IDR function depends on two distinct but related properties: sequence and chemical specificity. Whereas sequence specificity operates via binding motifs and depends on the precise order and identity of residues, chemical specificity reflects the sequence-encoded chemistry of multivalent interactions across an IDR and depends on local and global chemical properties. Unexpectedly, a binding motif essential in the wild-type IDR can be removed when compensatory changes to the sequence chemistry are introduced, highlighting the orthogonality and interoperability of these properties, and expanding the sequence space compatible with function. Our results provide a general framework for the functional constraints on IDR evolution.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Sequence (biology) ; Conserved Sequence ; Sequence Space ; Function (biology) ; Orthogonality ; Sequence Motif ; Peptide Sequence ; Sequence Alignment; General Regulatory Factors; Phase-separation; Transactivator Potentiation; Binding Factor-1; Yeast; Chromatin; Transcription; Dna; Domain; Abf1
ISSN (print) / ISBN 1465-7392
e-ISSN 1476-4679
Journal Nature Cell Biology
Quellenangaben Volume: 28, Issue: 2, Pages: 323-337 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Heidelberger Platz 3, Berlin, 14197, Germany
Reviewing status Peer reviewed
Institute(s) Institute of Functional Epigenetics (IFE)
Grants Deutsche Forschungsgemeinschaft (German Research Foundation)
National Science Foundation (NSF)