PT  - JOURNAL ARTICLE
AU  - Megan Leander
AU  - Yuchen Yuan
AU  - Anthony Meger
AU  - Qiang Cui
AU  - Srivatsan Raman
TI  - Functional Plasticity and Evolutionary Adaptation of Allosteric Regulation
AID  - 10.1101/2020.02.10.942417
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.10.942417
4099  - http://biorxiv.org/content/early/2020/02/11/2020.02.10.942417.short
4100  - http://biorxiv.org/content/early/2020/02/11/2020.02.10.942417.full
AB  - 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.