Role of kinetic intermediates in the folding of leech carboxypeptidase inhibitor.

The Journal of Biological Chemistry
Joan L ArolasSalvador Ventura

Abstract

The oxidative folding and reductive unfolding pathways of leech carboxypeptidase inhibitor (LCI; four disulfides) have been characterized in this work by structural and kinetic analysis of the acid-trapped folding intermediates. The oxidative folding of reduced and denatured LCI proceeds rapidly through a sequential flow of 1-, 2-, 3-, and 4-disulfide (scrambled) species to reach the native form. Folding intermediates of LCI comprise two predominant 3-disulfide species (designated as III-A and III-B) and a heterogeneous population of scrambled isomers that consecutively accumulate along the folding reaction. Our study reveals that forms III-A and III-B exclusively contain native disulfide bonds and correspond to stable and partially structured species that interconvert, reaching an equilibrium prior to the formation of the scrambled isomers. Given that these intermediates act as kinetic traps during the oxidative folding, their accumulation is prevented when they are destabilized, thus leading to a significant acceleration of the folding kinetics. III-A and III-B forms appear to have both native disulfides bonds and free thiols similarly protected from the solvent; major structural rearrangements through the formation of scramb...Continue Reading

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Citations

Nov 17, 2007·Antioxidants & Redox Signaling·Joan L ArolasChristian P Sommerhoff
Sep 4, 2010·Antioxidants & Redox Signaling·Joan L Arolas, Salvador Ventura
Oct 12, 2013·PloS One·Wen-Jun HeNing-Hua Tan
Mar 19, 2014·Antioxidants & Redox Signaling·Hugo FragaSalvador Ventura
May 19, 2012·The FEBS Journal·Mahesh Narayan
Apr 8, 2006·Trends in Biochemical Sciences·Joan L ArolasSalvador Ventura
Jun 9, 2006·The Journal of Biological Chemistry·Joan L ArolasJuan J Calvete
Oct 16, 2008·Archives of Biochemistry and Biophysics·Jui-Yoa ChangRick A Wetsel

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