Conformational buffering underlies functional selection in intrinsically disordered protein regions

GONZÁLEZ-FOUTEL, NICOLÁS S.; GLAVINA, JULIANA; BORCHERDS, WADE; SAFRANCHIK, MATÍAS; BARRERA-VILARMAU, SUSANA; SAGAR, AMIN; ESTAÑA, ALEJANDRO; BAROZET, AMELIE; GARRONE, NICOLÁS AGUSTÍN; FERNANDEZ-BALLESTER, GREGORIO; BLANES-MIRA, CLARA; SANCHEZ, IGNACIO E.; DE PRAT-GAY, GONZALO; CORTES, JUAN; BERNADÓ, PAU; PAPPU, ROHIT V.; HOLEHOUSE, ALEX S.; DAUGHDRILL, GARY W.; CHEMES, LUCIA B

NATURE STRUCTURAL & MOLECULAR BIOLOGY

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2022

1545-9985

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 binding to Rb 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 promote preservation or elimination of the tethering mechanism. indicating that both conformational buffering and motif-linker coevolution are responsible for robust functional encoding in hypervariable disordered linkers.