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Conformational buffering underlies functional selection in intrinsically disordered protein regions
Open accessPublished 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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Metadata
- 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.
- ORCID
- Venue
- Nature Structural & Molecular Biology
- Published
- 2022-08
- Volume
- 29
- Issue
- 8
- Pages
- 781-790
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC10262780
- OpenAlex
- W4291018995
- Cited by
- 118
- References
- 106
- Citations by year
- 2026: 22 · 2025: 34 · 2024: 22 · 2023: 30 · 2022: 8
- FWCI
- 7.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- 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
- Physical Sciences › Chemistry › Organic Chemistry › 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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