Cited by 118Protein Structure and DynamicsGenomics and Chromatin DynamicsChemical Synthesis and Analysis

Conformational buffering underlies functional selection in intrinsically disordered protein regions

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González-Foutel, Nicolás S., Glavina, Juliana, Borcherds, Wade M., Safranchik, Matías, Barrera-Vilarmau, Susana, Sagar, Amin, Estaña, Alejandro, Barozet, Amelie +11 more·2022·Nature Structural & Molecular Biology

Published version of a preprint

Abstract

Many disordered proteins conserve essential functions in the face of extensive sequence variation, making it challenging to identify the mechanisms responsible for functional selection. Here we identify the molecular mechanism of functional selection for the disordered adenovirus early gene 1A (E1A) protein. E1A competes with host factors to bind the retinoblastoma (Rb) protein, subverting cell cycle regulation. We show that two binding motifs tethered by a hypervariable disordered linker drive picomolar affinity Rb binding and host factor displacement. Compensatory changes in amino acid sequence composition and sequence length lead to conservation of optimal tethering across a large family of E1A linkers. We refer to this compensatory mechanism as conformational buffering. We also detect coevolution of the motifs and linker, which can preserve or eliminate the tethering mechanism. Conformational buffering and motif-linker coevolution explain robust functional encoding within hypervariable disordered linkers and could underlie functional selection of many disordered protein regions.

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Authors
González-Foutel, N. S., Glavina, J., Borcherds, W. M., Safranchik, M., Barrera-Vilarmau, S., Sagar, A., Estaña, A., Barozet, A., Garrone, N. A., Fernandez-Ballester, G., Blanes-Mira, C., Sánchez, I. E., de Prat-Gay, G., Cortés, J., Bernadó, P., Pappu, R. V., Holehouse, A. S., Daughdrill, G. W., & Chemes, L. B.
Affiliations
  • Consejo Nacional de Investigaciones Científicas y Técnicas (AR)
  • University of South Florida (US)
  • Consejo Superior de Investigaciones Científicas (ES)
  • Centre National de la Recherche Scientifique (FR)
  • Universitat de Miguel Hernández d'Elx (ES)
  • Washington University in St. Louis (US)
Corresponding author
  • Pappu, Rohit V.
  • Holehouse, Alex S.
  • Daughdrill, Gary W.
Venue
Nature Structural & Molecular Biology
Published
2022-08
Volume
29
Issue
8
Pages
781-790
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
OpenAlex
W4291018995
Cited by
118
References
106
Citations by year
2026: 22 · 2025: 34 · 2024: 22 · 2023: 30 · 2022: 8 · 2021: 2
FWCI
7.67
Type
journal article
Language
en
Open access
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
  • HAL (submittedVersion, other-oa)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, other-oa)
Funders
  • National Science Foundation (1614766)
  • Florida Department of Health (20B17)
  • Agence Nationale de la Recherche (2017-, 10-LABX-12-01, ANR-10-INBS-04-01, ANR-10- INBS-05, ANR-10-LABX-12-01, 10-INBS-04-01, ANR‐10_INBS‐04, ANR-10, ANR-10-LABX-0012, ANR-10-INBS-0004, ANR-10-INBS-0005)
  • Consejo Nacional de Investigaciones Científicas y Técnicas
  • Ministerio de Ciencia e Innovación (RTI2018-097189-C2-1)
  • Laboratoire d'Excellence EpiGenMed (ANR-10-LABX-12-01)
  • National Institutes of Health
  • Deutsches Elektronen-Synchrotron
  • Agencia Nacional de Promoción Científica y Tecnológica (2017/1924, CONICET)
  • National Cancer Institute (R01CA141244)
  • National Institute of General Medical Sciences (R01GM115556)
  • National Institute of Neurological Disorders and Stroke (R01NS056114)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords
intrinsically disordered proteins, functional selection, adenovirus E1A, retinoblastoma protein, protein-protein binding, cell cycle regulation, protein coevolution
MeSH terms
Protein Domains, Amino Acid Sequence, Protein Binding, Retinoblastoma Protein, Adenovirus E1A Proteins, Intrinsically Disordered Proteins

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