Interactions Causing the Kinetic Trap in Serpin Protein Folding
Conformational transition is fundamental to the mechanism of functional regulation in proteins, and serpins (serine protease inhibitors) can provide insight into this process. Serpins are metastable in their native forms, and they ordinarily undergo conformational transition to a stable state only w...
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Published in | The Journal of biological chemistry Vol. 277; no. 48; pp. 46347 - 46354 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Biochemistry and Molecular Biology
29.11.2002
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Subjects | |
Online Access | Get full text |
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Summary: | Conformational transition is fundamental to the mechanism of functional regulation in proteins, and serpins (serine protease
inhibitors) can provide insight into this process. Serpins are metastable in their native forms, and they ordinarily undergo
conformational transition to a stable state only when they form a tight complex with target proteases. The metastable native
form is thus considered to be a kinetically trapped folding intermediate. We sought to understand the nature of the serpin
kinetic trap as a step toward discovering how conformational transition is regulated. We found that mutations of the B/C β-barrel
of native α 1 -antitrypsin, a prototypical serpin, allowed conversion of the molecule into a more stable state. A 2.2 Ã
resolution crystal
structure of the stable form (PDB code, 1IZ2 ) showed that the reactive site loop is inserted into an A β-sheet, as in the latent plasminogen activator inhibitor-1. Mutational
analyses suggest strongly that interactions not found in the final stable form cause the kinetic trap in serpin protein folding. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M207682200 |