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 language | English (US) |
|---|---|
| Article number | 20170184 |
| Journal | Philosophical Transactions of the Royal Society B: Biological Sciences |
| Volume | 373 |
| Issue number | 1749 |
| DOIs | |
| State | Published - Jun 19 2018 |
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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 journal › Article
}
TY - JOUR
T1 - Ancient thioredoxins evolved to modern-day stability–function requirement by altering native state ensemble
AU - Modi, Tushar
AU - Huihui, Jonathan
AU - Ghosh, Kingshuk
AU - Ozkan, Sefika
PY - 2018/6/19
Y1 - 2018/6/19
N2 - 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’.
AB - 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’.
KW - Dynamic flexibility index
KW - Evolution
KW - Molecular dynamics
KW - Native state ensemble
KW - Protein conformational dynamics
KW - Thioredoxin
UR - http://www.scopus.com/inward/record.url?scp=85045646495&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045646495&partnerID=8YFLogxK
U2 - 10.1098/rstb.2017.0184
DO - 10.1098/rstb.2017.0184
M3 - Article
C2 - 29735738
AN - SCOPUS:85045646495
VL - 373
JO - Philosophical Transactions of the Royal Society B: Biological Sciences
JF - Philosophical Transactions of the Royal Society B: Biological Sciences
SN - 0800-4622
IS - 1749
M1 - 20170184
ER -