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Functional plasticity and evolutionary adaptation of allosteric regulation.

ABSTRACT: Allostery is a fundamental regulatory mechanism of protein function. Despite notable advances, understanding the molecular determinants of allostery remains an elusive goal. Our current knowledge of allostery is principally shaped by a structure-centric view, which makes it difficult to understand the decentralized character of allostery. We present a function-centric approach using deep mutational scanning to elucidate the molecular basis and underlying functional landscape of allostery. We show that allosteric signaling exhibits a high degree of functional plasticity and redundancy through myriad mutational pathways. Residues critical for allosteric signaling are surprisingly poorly conserved while those required for structural integrity are highly conserved, suggesting evolutionary pressure to preserve fold over function. Our results suggest multiple solutions to the thermodynamic conditions of cooperativity, in contrast to the common view of a finely tuned allosteric residue network maintained under selection.

SUBMITTER: Leander M

PROVIDER: S-EPMC7568325 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Functional plasticity and evolutionary adaptation of allosteric regulation.

Leander Megan M Yuan Yuchen Y Meger Anthony A Cui Qiang Q Raman Srivatsan S

Proceedings of the National Academy of Sciences of the United States of America 20200930 41

Allostery is a fundamental regulatory mechanism of protein function. Despite notable advances, understanding the molecular determinants of allostery remains an elusive goal. Our current knowledge of allostery is principally shaped by a structure-centric view, which makes it difficult to understand the decentralized character of allostery. We present a function-centric approach using deep mutational scanning to elucidate the molecular basis and underlying functional landscape of allostery. We sho ...[more]

PMID: 32999067

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Dataset Information

Functional plasticity and evolutionary adaptation of allosteric regulation.

Publications

Functional plasticity and evolutionary adaptation of allosteric regulation.

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