The Partially Folded Conformation of the Cys-30 Cys-51 Intermediate in the Disulfide Folding Pathway of Bovine Pancreatic Trypsin Inhibitor

• Published in: Proceedings of the National Academy of Sciences - PNAS 1992-08, Vol.89 (15), p.6775-6779
• Main Authors: Carlo P. M. van Mierlo, Darby, Nigel J., Creighton, Thomas E.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Aprotinin - chemistry; Biochemistry; Biological and medical sciences; bovine pancreatic trypsin inhibitor; Cattle; Chemical equilibrium; conformation; Conformational dynamics in molecular biology; Cysteine; disulfide bonds; Disulfides; Disulfides - chemistry; folding; Fundamental and applied biological sciences. Psychology; Hydrogen; Hydrogen bonds; Kinetics; Low temperature; Magnetic Resonance Spectroscopy - methods; Medical research; Models, Molecular; Molecular biophysics; Molecules; N.M.R; Protein Conformation; Protein folding; Proteins; Protons; Trypsin inhibitors; Ungulates
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.89.15.6775

The best-characterized protein folding pathway is that of bovine pancreatic trypsin inhibitor, which folds from the reduced form through a series of disulfide bond intermediates. The crucial one-disulfide intermediate of bovine pancreatic trypsin inhibitor with the disulfide bond between Cys-30 and Cys-51 is shown here to have a partially folded conformation in which the major elements of secondary structure interact via a core of apolar side chains, which resembles part of the native conformation. The stability of this structure can account for the predominance of this one-disulfide intermediate during folding. Much of the remaining one-third of the polypeptide chain, in particular the N-terminal 14 residues, is largely disordered; this accounts for the ability of this intermediate to form readily any of the three possible second disulfide bonds involving Cys-5, -14, and -38. The partially folded conformation of this intermediate provides direct evidence for the importance of native-like interactions between elements of secondary structure in directing protein folding, which is assumed in many studies.