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- Title
Local Transient Unfolding of Native State PAI-1 Associated with Serpin Metastability.
- Authors
Trelle, Morten B.; Madsen, Jeppe B.; Andreasen, Peter A.; Jørgensen, Thomas J. D.
- Abstract
The metastability of the native fold makes serpin (serine protease inhibitor) proteins prone to pathological conformational change, often by insertion of an extra β-strand into the central β-sheet A. How this insertion is made possible is a hitherto unresolved question. By the use of advanced hydrogen/deuterium-exchange mass spectrometry (HDX-MS) it is shown that the serpin plasminogen activator inhibitor 1 (PAI-1) transiently unfolds under native condition, on a second-to-minute time scale. The unfolding regions comprise β-strand 5A as well as the underlying hydrophobic core, including β-strand 6B and parts of helices A, B, and C. Based thereon, a mechanism is proposed by which PAI-1 makes transitions through progressively more unfolded states along the reaction coordinate to the inactive, so-called latent form. Our results highlight the profound utility of HDX-MS in detecting sparsely populated, transiently unfolded protein states.
- Subjects
MOLECULAR dynamics method of protein folding; ISOTOPE exchange reactions; SERPINS; MASS spectrometry; PROTEIN structure; STRUCTURAL proteomics
- Publication
Angewandte Chemie, 2014, Vol 126, Issue 37, p9909
- ISSN
0044-8249
- Publication type
Article
- DOI
10.1002/ange.201402796