The sequence-ensemble relationships in fuzzy protein complexes

San Hadzi, Remy Loris, Jurij Lah

Onderzoeksoutput: Articlepeer review

5 Citaten (Scopus)
9 Downloads (Pure)


Intrinsically disordered proteins (IDPs) interact with globular proteins through variety of mechanisms, resulting in structurally heterogeneous ensembles known as fuzzy complexes. While there exists a reasonable comprehension on how IDP sequence determines the unbound IDP ensemble, little is known about what shapes the structural ensembles of IDPs bound to their targets. Using a statistical-thermodynamic model we show that the target-bound ensembles are determined by a simple code combining IDP sequence and the distribution of IDP-target interaction hotspots. These two parameters define the conformational phase space target-bound IDPs and rationalize the observed structural heterogeneity of fuzzy complexes. The presented model successfully reproduces dynamical signatures form the NMR relaxation experiments and changes in the average helicity and interaction affinity induced by mutations. The model explains how target-bound IDP ensembles modulate their conformation in response mutations in order to achieve an optimal balance between conformational freedom and interaction energy. Taken together, the presented sequence-ensemble relationship of fuzzy complexes explains the different manifestations of IDP disorder in folding-upon-binding processes.
Originele taal-2English
TijdschriftProc Natl Acad Sci USA
Nummer van het tijdschrift37
StatusPublished - 14 sep 2021

Bibliografische nota

Funding Information:
ACKNOWLEDGMENTS. This work was supported by the Grants P1-0201 and J1-1706 from the Slovenian Research Agency to S.H. and J.L. and by Grants G003320N from Fonds voor Wetenschappelijk Onderzoek–Vlaanderen and SRP13 from the Onderzoeksraad of the Vrije Universiteit Brussel to R.L. We are grateful to Mojca Hunski and Uroš Zavrtanik for help with the preparation of the final version of the manuscript and help with the ITC experiments and to Prof. Dr. Roger Pain for critically reading the manuscript.

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Copyright 2022 Elsevier B.V., All rights reserved.


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