A parametrized two-domain thermodynamic model explains diverse mutational effects on protein allostery.

ABSTRACT: New experimental findings continue to challenge our understanding of protein allostery. Recent deep mutational scanning study showed that allosteric hotspots in the tetracycline repressor (TetR) and its homologous transcriptional factors are broadly distributed rather than spanning well-defined structural pathways as often assumed. Moreover, hotspot mutation-induced allostery loss was rescued by distributed additional mutations in a degenerate fashion. Here, we develop a two-domain thermodynamic model for TetR, which readily rationalizes these intriguing observations. The model accurately captures the in vivo activities of various mutants with changes in physically transparent parameters, allowing the data-based quantification of mutational effects using statistical inference. Our analysis

SUBMITTER: Liu Z 

PROVIDER: S-EPMC10473640 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature