Structural basis of latency in plasminogen activator inhibitor-1

James Mottonen, Arne Strand, Jindrich Symersky, Robert M. Sweet, Dennis E. Danley, Kieran F. Geoghegan, Robert D. Gerard, Elizabeth J. Goldsmith

Research output: Contribution to journalArticle

507 Scopus citations

Abstract

HUMAN plasminogen activator inhibitor-1 (PAI-1)1,2 is the fast-acting inhibitor of tissue plasminogen activator and urokinase3 and is a member of the serpin family of protease inhibitors4. Serpins normally form complexes with their target proteases that dissociate very slowly as cleaved species and then fold into a highly stable inactive state5 in which the residues that flank the scissile bond (P1 and P1'; ref. 6) are separated by about 70 Å (refs 7-9). PAI-1 also spontaneously folds into a stable10 inactive state without cleavage; this state is termed 'latent' because inhibitory activity can be restored through denaturation and renaturation2,10. Here we report the structure of intact latent PAI-1 determined by single-crystal X-ray diffraction to 2.6 Å resolution. The three-dimensional structure reveals that residues on the N-terminal side of the primary recognition site are inserted as a central strand of the largest βsheet, in positions similar to the corresponding residues in the cleaved form of the serpin α1proteinase inhibitor (α1-PI)7. Residues C-terminal to the recognition site occupy positions on the surface of the molecule distinct from those of the corresponding residues in cleaved serpins7-9 or in the intact inactive serpin homologue, ovalbumin11, and its cleavage product, plakal-bumin12. The structure of latent PAI-1 is similar to one formed after cleavage in other serpins, and the stability of both latent PAI-1 and cleaved serpins may be derived from the same structural features13,14.

Original languageEnglish (US)
Pages (from-to)270-273
Number of pages4
JournalNature
Volume355
Issue number6357
DOIs
StatePublished - Jan 1 1992

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Structural basis of latency in plasminogen activator inhibitor-1'. Together they form a unique fingerprint.

  • Cite this

    Mottonen, J., Strand, A., Symersky, J., Sweet, R. M., Danley, D. E., Geoghegan, K. F., Gerard, R. D., & Goldsmith, E. J. (1992). Structural basis of latency in plasminogen activator inhibitor-1. Nature, 355(6357), 270-273. https://doi.org/10.1038/355270a0