Conformational Buffering Underlies Functional Selection in Intrinsically Disordered Protein Regions
Document Type
Article
Publication Date
2022
Digital Object Identifier (DOI)
https://doi.org/10.1038/s41594-022-00811-w
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 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.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Nature Structural & Molecular Biology, v. 29, p. 781-790
Scholar Commons Citation
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.; and Chemes, Lucía B., "Conformational Buffering Underlies Functional Selection in Intrinsically Disordered Protein Regions" (2022). Molecular Biosciences Faculty Publications. 144.
https://digitalcommons.usf.edu/bcm_facpub/144
