title: Protease inhibitors as models for the study of oxidative folding.
abstract: The correct balance between proteases and their natural protein inhibitors is of great importance in living systems. Protease inhibitors usually comprise small folds that are crosslinked by a high number of disulfide bonds, making them perfect models for the study of oxidative folding. To date, the oxidative folding of numerous protease inhibitors has been analyzed, revealing a great diversity of folding pathways that differ mainly in the heterogeneity and native disulfide-bond content of their intermediates. The two extremes of this diversity are represented by bovine pancreatic trypsin inhibitor and hirudin, which fold, respectively, via few native intermediates and heterogeneous scrambled isomers. Other proteins, such as leech carboxypeptidase inhibitor, share characteristics of both models displaying mixed folding pathways. The study of the oxidative folding of two-domain inhibitors, such as secretory leukocyte protease inhibitor, tick carboxypeptidase inhibitor, and Ascaris carboxypeptidase inhibitor, has provided some clues about how two-domain protease inhibitors may fold, that is, either by folding each domain autonomously or with one domain assisting in the folding of the other. Finally, the recent determination of the structures of the major intermediates of protease inhibitors has shed light on the molecular mechanisms guiding the oxidative folding of small disulfide-rich proteins.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Institut de Biotecnologia i Biomedicina, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain.
authors.forename: Joan L
authors.initials: JL
authors.lastname: Arolas
authors.forename: Salvador
authors.initials: S
authors.lastname: Ventura
mesh_terms: D000818:Animals; D007611:Aprotinin / Q000737:chemistry* / Q000378:metabolism*; D006629:Hirudins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D010084:Oxidation-Reduction; D017510:Protein Folding
chemical_list: D006629:Hirudins; D007611:Aprotinin