Ancient thioredoxins evolved to modern-day stability–function requirement by altering native state ensemble

Tushar Modi, Jonathan Huihui, Kingshuk Ghosh, Sefika Ozkan

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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 α3, α4 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 low pH with 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’.

Original languageEnglish (US)
Article number20170184
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Volume373
Issue number1749
DOIs
StatePublished - Jun 19 2018

Fingerprint

Thioredoxins
protein
Proteins
proteins
Catalytic Domain
Mammals
Archaea
melting point
Hinges
catalytic activity
active sites
Freezing
Cluster Analysis
Melting point
Catalyst activity
comparative study
mammal
amino acid
melting
perturbation

Keywords

  • Dynamic flexibility index
  • Evolution
  • Molecular dynamics
  • Native state ensemble
  • Protein conformational dynamics
  • Thioredoxin

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Ancient thioredoxins evolved to modern-day stability–function requirement by altering native state ensemble. / Modi, Tushar; Huihui, Jonathan; Ghosh, Kingshuk; Ozkan, Sefika.

In: Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 373, No. 1749, 20170184, 19.06.2018.

Research output: Contribution to journalArticle

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