Conformational buffering underlies functional selection in intrinsically disordered protein regions

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)...

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Detalles Bibliográficos
Autores: González-Foutel, Nicolás S., Glavina, Juliana, Borcherds, Wade M., Safranchik, Matías, Barrera-Vilarmau, Susana, Sagar, Amin, Estaña, Alejandro, Barozet, Amélie, Garrone, Nicolás A., Fernandez-Ballester, Gregorio, Blanes-Mira, Clara, Sánchez, Ignacio E., Prat-Gay, Gonzalo de, Cortés, Juan, Bernadó, Pau, Pappu, Rohit V., Holehouse, Alex S., Daughdrill, Gary W., Chemes, Lucía B.
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2022
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/278751
Acceso en línea:http://hdl.handle.net/10261/278751
https://api.elsevier.com/content/abstract/scopus_id/85135867846
Access Level:acceso abierto
Palabra clave:Proteins
Intrinsically disordered protein regions
Descripción
Sumario: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.

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