文章基本信息

标题：Folding mechanism of the metastable serpin α1-antitrypsin
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作者：Yuko Tsutsui ; Richard Dela Cruz ; Patrick L. Wintrode 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2012
卷号：109
期号：12
页码：4467-4472
DOI：10.1073/pnas.1109125109
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：The misfolding of serpins is linked to several genetic disorders including emphysema, thrombosis, and dementia. During folding, inhibitory serpins are kinetically trapped in a metastable state in which a stretch of residues near the C terminus of the molecule are exposed to solvent as a flexible loop (the reactive center loop). When they inhibit target proteases, serpins transition to a stable state in which the reactive center loop forms part of a six-stranded {beta}-sheet. Here, we use hydrogen-deuterium exchange mass spectrometry to monitor region-specific folding of the canonical serpin human 1-antitrypsin (1-AT). We find large differences in the folding kinetics of different regions. A key region in the metastable [->] stable transition, {beta}-strand 5A, shows a lag phase of nearly 350 s. In contrast, the "B-C barrel" region shows no lag phase and the incorporation of the C-terminal residues into {beta}-sheets B and C is largely complete before the center of {beta}-sheet A begins to fold. We propose this as the mechanism for trapping 1-AT in a metastable form. Additionally, this separation of timescales in the folding of different regions suggests a mechanism by which 1-AT avoids polymerization during folding.
关键词：hydrogen exchange ; misfolding disease ; protein folding