期刊
PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES
卷 373, 期 1749, 页码 -出版社
ROYAL SOC
DOI: 10.1098/rstb.2017.0184
关键词
evolution; thioredoxin; native state ensemble; dynamic flexibility index; molecular dynamics; protein conformational dynamics
类别
资金
- NSF-MCB Award by RCSA [1715591]
- RCSA
- Gordon & Betty Moore Foundation
- National Science Foundation (NSF) [1149992]
- Research Corporation for Science Advancement
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1715591] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1149992] Funding Source: National Science Foundation
Thioredoxins (THRXs)-small globular proteins that reduce other proteins-are ubiquitous in all forms of life, from Archaea to mammals. Although ancestral thioredoxins share sequential and structural similarity with the modern-day (extant) homologues, they exhibit significantly different functional activity and stability. We investigate this puzzle by comparative studies of their (ancient and modern-day THRXs') native state ensemble, as quantified by the dynamic flexibility index (DFI), a metric for the relative resilience of an amino acid to perturbations in the rest of the protein. Clustering proteins using DFI profiles strongly resemble an alternative classification scheme based on their activity and stability. The DFI profiles of the extant proteins are substantially different around the alpha 3, alpha 4 helices and catalytic regions. Likewise, allosteric coupling of the active site with the rest of the protein is different between ancient and extant THRXs, possibly explaining the decreased catalytic activity at lowp Hwith evolution. At a global level, we note that the population of low-flexibility (called hinges) and high-flexibility sites increases with evolution. The heterogeneity (quantified by the variance) in DFI distribution increases with the decrease in the melting temperature typically associated with the evolution of ancient proteins to their modern-day counterparts. This article is part of a discussion meeting issue 'Allostery and molecular machines'.
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