Steve Ealick's Research Group
Abstract:Xu G, Narayan M, Kurinov I, Ripoll DR, Welker E, Khalili M, Ealick SE, and Scheraga HA. A Localized Specific Interaction Alters the Unfolding Pathways of Structural Homologues. J. Am. Chem. Soc. 128:1204-1213 (2006).
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
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.
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