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The length of the reactive center loop modulates the latency transition of plasminogen activator inhibitor-1

Department of Molecular Biology, Research Center for Conformational Degenerative Diseases, Sejong University, Seoul 143-747, Korea

(RECEIVED August 24, 2004; FINAL REVISION September 13, 2004; ACCEPTED September 14, 2004)

Plasminogen activator inhibitor-1 (PAI-1) belongs to the serine protease inhibitor (serpin) protein family, which has a common tertiary structure consisting of three -sheets and several -helices. Despite the similarity of its structure with those of other serpins, PAI-1 is unique in its conformational lability, which allows the conversion of the metastable active form to a more stable latent conformation under physiological conditions. For the conformational conversion to occur, the reactive center loop (RCL) of PAI-1 must be mobilized and inserted into the major -sheet, A sheet. In an effort to understand how the structural conversion is regulated in this conformationally labile serpin, we modulated the length of the RCL of PAI-1. We show that releasing the constraint on the RCL by extension of the loop facilitates a conformational transition of PAI-1 to a stable state. Biochemical data strongly suggest that the stabilization of the transformed conformation is owing to the insertion of the RCL into A -sheet, as in the known latent form. In contrast, reducing the loop length drastically retards the conformational change. The results clearly show that the constraint on the RCL is a factor that regulates the conformational transition of PAI-1.

Keywords: conformational transition; kinetic trap; latency transition; loop length; plasminogen activator inhibitor-1; protein folding; serpin

Abbreviations: PAI-1, plasminogen activator inhibitor-1 • serpin, serine protease inhibitor • RCL, reactive center loop • tPA, tissue-type plasminogen activator • uPA, urokinase-type plasminogen activator

Article published online ahead of print. Article and publication date are at http://www.proteinscience.org/cgi/doi/10.1110/ps.041063705.

Reprint requests to: Hana Im, Department of Molecular Biology, Research Center for Conformational Degenerative Diseases, Sejong University, 98 Gunja-dong, Kwangjin-gu, Seoul 143-747, Korea; e-mail: hanaim{at}sejong.ac.kr; fax: 82-2-3408-3661.

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