A localized specific interaction alters the unfolding pathways of structural homologues

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

Research output: Contribution to journalArticle

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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Pancreatic Ribonuclease
Proteins
Disulfides
Protein Unfolding
Molecular Dynamics Simulation
Statistical Factor Analysis
Molecular dynamics
Stabilization
Crystal structure
Modulation
Temperature
Computer simulation
Ribonucleases

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

A localized specific interaction alters the unfolding pathways of structural homologues. / Xu, Guoqiang; Narayan, Mahesh; Kurinov, Igor; Ripoll, Daniel R.; Welker, E.; Khalili, Mey; Ealick, Steven E.; Scheraga, Harold A.

In: Journal of the American Chemical Society, Vol. 128, No. 4, 01.02.2006, p. 1204-1213.

Research output: Contribution to journalArticle

Xu, G, Narayan, M, Kurinov, I, Ripoll, DR, Welker, E, Khalili, M, Ealick, SE & Scheraga, HA 2006, 'A localized specific interaction alters the unfolding pathways of structural homologues', Journal of the American Chemical Society, vol. 128, no. 4, pp. 1204-1213. https://doi.org/10.1021/ja055313e
Xu, Guoqiang ; Narayan, Mahesh ; Kurinov, Igor ; Ripoll, Daniel R. ; Welker, E. ; Khalili, Mey ; Ealick, Steven E. ; Scheraga, Harold A. / A localized specific interaction alters the unfolding pathways of structural homologues. In: Journal of the American Chemical Society. 2006 ; Vol. 128, No. 4. pp. 1204-1213.
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