Multivalency enables unidirectional switch-like competition between intrinsically disordered proteins

Author:

Berlow Rebecca B.12ORCID,Dyson H. Jane12ORCID,Wright Peter E.12ORCID

Affiliation:

1. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037

2. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037

Abstract

Significance Intrinsically disordered proteins must frequently compete for binding to shared interaction hubs to perform their cellular functions. Here, we describe the mechanism by which two disordered proteins that regulate the transcriptional response to hypoxia compete for binding to the folded TAZ1 domain of the transcriptional coactivators CBP and p300. CITED2, a negative feedback regulator of HIF-1α, displaces HIF-1α from TAZ1 in a unidirectional, switch-like manner. Efficient competition for binding of the TAZ1 domain is highly dependent on the flexibility and multivalency of the HIF-1α and CITED2 activation domains. Differences in the strength of coupling of the CITED2 and HIF-1α binding motifs are key determinants of unidirectionality and underscore the role of multivalency in regulation of cellular processes by disordered proteins.

Funder

American Cancer Society

HHS | NIH | National Cancer Institute

HHS | NIH | National Institute of General Medical Sciences

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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