BECAS
GARRONE NicolÁs AgustÍn
artículos
Título:
Conformational buffering underlies functional selection in intrinsically disordered protein regions
Autor/es:
GONZÁLEZ-FOUTEL, NICOLÁS S.; GLAVINA, JULIANA; BORCHERDS, WADE M.; SAFRANCHIK, MATÍAS; BARRERA-VILARMAU, SUSANA; SAGAR, AMIN; ESTAÑA, ALEJANDRO; BAROZET, AMELIE; GARRONE, NICOLÁS A.; FERNANDEZ-BALLESTER, GREGORIO; BLANES-MIRA, CLARA; SÁNCHEZ, IGNACIO E.; DE PRAT-GAY, GONZALO; CORTÉS, JUAN; BERNADÓ, PAU; PAPPU, ROHIT V.; HOLEHOUSE, ALEX S.; DAUGHDRILL, GARY W.; CHEMES, LUCÍA B.
Revista:
Nature Structural and Molecular Biology
Editorial:
Nature Research
Referencias:
Año: 2022 vol. 29 p. 781 - 790
ISSN:
1545-9993
Resumen:
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 motiflinker coevolution explain robust functional encoding within hypervariable disordered linkers and could underlie functional selection of many disordered protein regions.