期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 29, 期 8, 页码 781-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00811-w
关键词
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资金
- Agencia Nacional de Promocion Cientifica y Tecnologica (ANPCyT) [2013-1895, 2017-1924, 2016-4605, 2012-2550, 2015-1213]
- US National Institutes of Health [GM115556, CA141244, 5R01NS056114]
- Florida Department of Health (FLDOH) [20B17]
- US National Science Foundation [MCB-1614766]
- USF Nexus Initiative
- USF College of Arts and Sciences
- Labex EpiGenMed (Investissements d'avenir) program [ANR-10-LABX-12-01]
- French National Research Agency [ANR-10-INBS-04-01, ANR-10-INBS-05]
- Spanish Ministerio de Ciencia y Universidades MICYU-FEDER [RTI2018-097189-C2-1]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET, Argentina)
- Fulbright Visiting Scholar Program
- Ministerio de Ciencia e Innovacion, Espana [BES-2013-063991, EEBB-I-16-11670]
- Longer Life Foundation: A RGA/Washington University Collaboration
- CALMIP supercomputing center [2016-P16032]
- Cluster of Scientific Computing of the Miguel Hernandez University
This study identifies the molecular mechanism of functional selection in disordered proteins and highlights the importance of conformational buffering and motif-linker coevolution for functional encoding.
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. Foutel et. al. identify conformational buffering as a mechanism for functional selection in intrinsically disordered protein regions that allows robust encoding of a tethering function by a hypervariable disordered linker through compensatory changes in sequence length and composition.
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