Coupling of domain swapping to kinetic stability in a thioredoxin mutant

Garcia-Pino, A.; Wahni, K.; Wyns, L.; Martinez-Rodriguez, S.; Messens, J.; Loris, R.

doi:10.1016/j.jmb.2008.11.040

Journal Article

PHPPUBDB-11995

Coupling of domain swapping to kinetic stability in a thioredoxin mutant

Garcia-Pino, A. ; Martinez-Rodriguez, S. ; Wahni, K. ; Wyns, L. ; Loris, R. ; Messens, J. (Corresponding author) ; DESY

2009
Elsevier Amsterdam [u.a.]

Journal of molecular biology 385, 1590-1599 (2009) [10.1016/j.jmb.2008.11.040]

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Please use a persistent id in citations: doi:10.1016/j.jmb.2008.11.040

Abstract: The thioredoxin (Trx) fold is a small monomeric domain that is ubiquitous in redox-active enzymes. Trxs are characterized by a typical WCGPC active-site sequence motif. A single active-site mutation of the tryptophan to an alanine in Staphylococcus aureus Trx converts the oxidized protein into a biologically inactive domain-swapped dimer. While the monomeric protein unfolds reversibly in a two-state manner, the oxidized dimeric form is kinetically stable and converts to the monomeric form upon refolding. After reduction, the half-life of the dimer decreases many orders of magnitude to ∼ 4.3 h, indicating that the active-site disulfide between $Cys{29}§ and $Cys{32}$ is an important determinant for the kinetics of unfolding. We propose kinetic stability as a possible evolutionary strategy in the evolution of multimeric proteins from their monomeric ancestors by domain swapping, which, for this biologically inactive Trx mutant, turned out to be an evolutionary dead end.

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