HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 35, 25416-25424, August 31, 2007

This Article Full Text Full Text (PDF) All Versions of this Article: 282/35/25416    most recent M702410200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Versteeg, H. H. Articles by Ruf, W. Search for Related Content PubMed PubMed Citation Articles by Versteeg, H. H. Articles by Ruf, W. Social Bookmarking                      What's this?

Tissue Factor Coagulant Function Is Enhanced by Protein-disulfide Isomerase Independent of Oxidoreductase Activity^*

From the Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

Protein-disulfide isomerase (PDI) switches tissue factor (TF) from coagulation to signaling by targeting the allosteric Cys¹⁸⁶–Cys²⁰⁹ disulfide. Here, we further characterize the interaction of purified PDI with TF. We find that PDI enhances factor VIIa-dependent substrate factor X activation 5–10-fold in the presence of wild-type, oxidized soluble TF but not TF mutants that contain an unpaired Cys¹⁸⁶ or Cys²⁰⁹. PDI-accelerated factor Xa generation was blocked by bacitracin but not influenced by inhibition of vicinal thiols, reduction of PDI, changes in redox gradients, or covalent thiol modification of reduced PDI by N-ethylmaleimide or methyl-methanethiosulfonate, which abolished PDI oxidoreductase but not chaperone activity. PDI had no effect on fully active TF on either negatively charged phospholipids or in activating detergent, indicating that PDI selectively acts upon cryptic TF to facilitate ternary complex formation and macromolecular substrate turnover. PDI activation was reduced upon mutation of TF residues in proximity to the macromolecular substrate binding site, consistent with a primary interaction of PDI with TF. PDI enhanced TF coagulant activity on microvesicles shed from cells, suggesting that PDI plays a role as an activating chaperone for circulating cryptic TF.

Received for publication, March 21, 2007 , and in revised form, July 5, 2007.

^* This work was supported by NHLBI, National Institutes of Health, Grant HL-31950 (to W. R.) and American Heart Association Grant 0625192Y (to H. H. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Immunology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037.Tel.: 858-784-2748; Fax: 858-784-8480; E-mail: ruf{at}scripps.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				C. C. Milsom, J. L. Yu, N. Mackman, J. Micallef, G. M. Anderson, A. Guha, and J. W. Rak Tissue Factor Regulation by Epidermal Growth Factor Receptor and Epithelial-to-Mesenchymal Transitions: Effect on Tumor Initiation and Angiogenesis Cancer Res., December 15, 2008; 68(24): 10068 - 10076. [Abstract] [Full Text] [PDF]

				B. Furie and B. C. Furie Mechanisms of Thrombus Formation N. Engl. J. Med., August 28, 2008; 359(9): 938 - 949. [Full Text] [PDF]

				H. Kothari, P. Sen, U. R. Pendurthi, and L. V. M. Rao Bovine protein disulfide isomerase-enhanced tissue factor coagulant function: is phospholipid contaminant in it the real culprit? Blood, March 15, 2008; 111(6): 3295 - 3296. [Full Text] [PDF]

				J. H. Morrissey Encryption remains cryptic Blood, December 1, 2007; 110(12): 3822 - 3823. [Full Text] [PDF]

				U. R. Pendurthi, S. Ghosh, S. K. Mandal, and L. V. M. Rao Tissue factor activation: is disulfide bond switching a regulatory mechanism? Blood, December 1, 2007; 110(12): 3900 - 3908. [Abstract] [Full Text] [PDF]