Conformational buffering underlies functional selection in intrinsically disordered protein regions.
Journal
Nature structural & molecular biology
ISSN: 1545-9985
Titre abrégé: Nat Struct Mol Biol
Pays: United States
ID NLM: 101186374
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
22
06
2021
accepted:
23
06
2022
pubmed:
11
8
2022
medline:
16
8
2022
entrez:
10
8
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 35948766
doi: 10.1038/s41594-022-00811-w
pii: 10.1038/s41594-022-00811-w
pmc: PMC10262780
mid: NIHMS1893822
doi:
Substances chimiques
Adenovirus E1A Proteins
0
Intrinsically Disordered Proteins
0
Retinoblastoma Protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
781-790Subventions
Organisme : NCI NIH HHS
ID : R01 CA141244
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM115556
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS056114
Pays : United States
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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