The FASEB Journal, Vol 10, 110-118, Copyright © 1996 by The Federation of American Societies for Experimental Biology

REVIEWS

The roles of partly folded intermediates in protein folding

TE Creighton, NJ Darby and J Kemmink
European Molecular Biology Laboratory, Heidelberg, Germany.

Proteins can fold very rapidly, undoubtedly because they do not do so simply by random searching. The stable, partly folded species that can be detected during protein refolding are, however, of uncertain kinetic significance. The available kinetic evidence indicates that the intermediates that are most responsible for the rapidity of folding are extremely unstable and not populated detectably; they are less extreme versions of the transition state for folding. Protein folding is most readily studied when it is coupled to disulfide formation, which has the advantages that the intermediates can be characterized in detail and their kinetic roles determined unambiguously. The most important aspects of the disulfide folding pathway of BPTI are understood to at least a first approximation, and several other protein disulfide folding pathways are known in outline. These pathways demonstrate that disulfide folding is not intrinsically different from that not involving disulfide formation. Partly folded conformations can increase the rate of folding somewhat by causing productive disulfide bonds to be populated preferentially, but the most important folding intermediates are not detectable. The essence of folding is to build up the cooperativity between the individual interactions that is necessary for a stable conformation.

This article has been cited by other articles:

				Q.-x. Hua, J. P. Mayer, W. Jia, J. Zhang, and M. A. Weiss The Folding Nucleus of the Insulin Superfamily: A FLEXIBLE PEPTIDE MODEL FORESHADOWS THE NATIVE STATE J. Biol. Chem., September 22, 2006; 281(38): 28131 - 28142. [Abstract] [Full Text] [PDF]

				J. L. Arolas, S. Bronsoms, S. Ventura, F. X. Aviles, and J. J. Calvete Characterizing the Tick Carboxypeptidase Inhibitor: MOLECULAR BASIS FOR ITS TWO-DOMAIN NATURE J. Biol. Chem., August 11, 2006; 281(32): 22906 - 22916. [Abstract] [Full Text] [PDF]

				J. L. Arolas, S. Bronsoms, J. Lorenzo, F. X. Aviles, J.-Y. Chang, and S. Ventura Role of Kinetic Intermediates in the Folding of Leech Carboxypeptidase Inhibitor J. Biol. Chem., September 3, 2004; 279(36): 37261 - 37270. [Abstract] [Full Text] [PDF]

				X.-Y. Jia, Z.-Y. Guo, Y. Wang, Y. Xu, S.-S. Duan, and Y.-M. Feng Peptide models of four possible insulin folding intermediates with two disulfides Protein Sci., November 1, 2003; 12(11): 2412 - 2419. [Abstract] [Full Text] [PDF]

				Z.-S. Qiao, C.-Y. Min, Q.-X. Hua, M. A. Weiss, and Y.-M. Feng In Vitro Refolding of Human Proinsulin. KINETIC INTERMEDIATES, PUTATIVE DISULFIDE-FORMING PATHWAY, FOLDING INITIATION SITE, AND POTENTIAL ROLE OF C-PEPTIDE IN FOLDING PROCESS J. Biol. Chem., May 9, 2003; 278(20): 17800 - 17809. [Abstract] [Full Text] [PDF]

				H. Yan, Z.-Y. Guo, X.-W. Gong, D. Xi, and Y.-M. Feng A peptide model of insulin folding intermediate with one disulfide Protein Sci., April 1, 2003; 12(4): 768 - 775. [Abstract] [Full Text] [PDF]

				M. Schwaller, B. Wilkinson, and H. F. Gilbert Reduction-Reoxidation Cycles Contribute to Catalysis of disulfide Isomerization by Protein-disulfide Isomerase J. Biol. Chem., February 21, 2003; 278(9): 7154 - 7159. [Abstract] [Full Text] [PDF]

				V. Singh and W. E. Merz Disulfide Bond Formation Is Not Required for Human Chorionic Gonadotropin Subunit Association. STUDIES WITH DITHIOTHREITOL IN JEG-3 CELLS J. Biol. Chem., April 14, 2000; 275(16): 11765 - 11770. [Abstract] [Full Text] [PDF]

				M. J. Pandya, P. B. Williams, C. E. Dempsey, P. R. Shewry, and A. R. Clarke Direct Kinetic Evidence for Folding via a Highly Compact, Misfolded State J. Biol. Chem., September 17, 1999; 274(38): 26828 - 26837. [Abstract] [Full Text] [PDF]

				V. Westphal, J. C. Spetzler, M. Meldal, U. Christensen, and J. R. Winther Kinetic Analysis of the Mechanism and Specificity of Protein-disulfide Isomerase Using Fluorescence-quenched Peptides J. Biol. Chem., September 25, 1998; 273(39): 24992 - 24999. [Abstract] [Full Text] [PDF]

				Z.-B. Zhu, T. P. Atkinson, and J. E. Volanakis A Novel Type II Complement C2 Deficiency Allele in an African-American Family J. Immunol., July 15, 1998; 161(2): 578 - 584. [Abstract] [Full Text] [PDF]

				M. Jacob, T. Schindler, J. Balbach, and F. X. Schmid Diffusion control in an elementary protein folding reaction PNAS, May 27, 1997; 94(11): 5622 - 5627. [Abstract] [Full Text] [PDF]

				R. W. Ruddon and E. Bedows Assisted Protein Folding J. Biol. Chem., February 7, 1997; 272(6): 3125 - 3128. [Full Text] [PDF]

				S. Scheuermann, B. Hambsch, L. Hesse, J. Stumm, C. Schmidt, D. Beher, T. A. Bayer, K. Beyreuther, and G. Multhaup Homodimerization of Amyloid Precursor Protein and Its Implication in the Amyloidogenic Pathway of Alzheimer's Disease J. Biol. Chem., August 31, 2001; 276(36): 33923 - 33929. [Abstract] [Full Text] [PDF]