Conformational buffering underlies functional selection in intrinsically disordered protein regions - LAAS - Laboratoire d'Analyse et d'Architecture des Systèmes Access content directly
Journal Articles Nature Structural and Molecular Biology Year : 2022

Conformational buffering underlies functional selection in intrinsically disordered protein regions

Amelie Barozet
Clara Blanes-Mira
Juan Cortés
Rohit Pappu
Alex Holehouse
Gary Daughdrill

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 co-evolution 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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Dates and versions

hal-03767337 , version 1 (01-09-2022)

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Nicolás González-Foutel, Juliana Glavina, Wade Borcherds, Matías Safranchik, Susana Barrera-Vilarmau, et al.. Conformational buffering underlies functional selection in intrinsically disordered protein regions. Nature Structural and Molecular Biology, 2022, 29 (8), pp.781-790. ⟨10.1038/s41594-022-00811-w⟩. ⟨hal-03767337⟩
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