A localized specific interaction alters the unfolding pathways of structural homologues

Guoqiang Xu, Mahesh Narayan, Igor Kurinov, Daniel R. Ripoll, Ervin Welker, Mey Khalili, Steven E. Ealick, Harold A. Scheraga

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19 Citations (Scopus)

Abstract

Reductive unfolding studies of proteins are designed to provide information about intramolecular interactions that govern the formation (and stabilization) of the native state and about folding/unfolding pathways. By mutating Tyr92 to G, A, or L in the model protein, bovine pancreatic ribonuclease A, and through analysis of temperature factors and molecular dynamics simulations of the crystal structures of these mutants, it is demonstrated that the markedly different reductive unfolding rates and pathways of ribonuclease A and its structural homologue onconase can be attributed to a single, localized, ring-stacking interaction between Tyr92 and Pro93 in the bovine variant. The fortuitous location of this specific stabilizing interaction in a disulfide-bond-containing loop region of ribonuclease A results in the localized modulation of protein dynamics that, in turn, enhances the susceptibility of the disulfide bond to reduction leading to an alteration in the reductive unfolding behavior of the homologues. These results have important implications for folding studies involving topological determinants to obtain folding/unfolding rates and pathways, for protein structure-function prediction through fold recognition, and for predicting proteolytic cleavage sites.

Original languageEnglish
Pages (from-to)1204-1213
Number of pages10
JournalJournal of the American Chemical Society
Volume128
Issue number4
DOIs
Publication statusPublished - Feb 1 2006

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ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Xu, G., Narayan, M., Kurinov, I., Ripoll, D. R., Welker, E., Khalili, M., Ealick, S. E., & Scheraga, H. A. (2006). A localized specific interaction alters the unfolding pathways of structural homologues. Journal of the American Chemical Society, 128(4), 1204-1213. https://doi.org/10.1021/ja055313e