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Prepublished online as a Blood First Edition Paper on July 24, 2003; DOI 10.1182/blood-2003-03-0949. This Article Full Text (PDF) All Versions of this Article: 2003-03-0949v1 102/10/3600    most recent Alert me when this article is cited Alert me if a correction is posted 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 Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bdeir, K. Articles by Cines, D. B Search for Related Content PubMed PubMed Citation Articles by Bdeir, K. Articles by Cines, D. B Social Bookmarking                   What's this? Submitted March 27, 2003 Accepted June 25, 2003 The kringle stabilizes urokinase binding to the urokinase receptor Khalil Bdeir, Alice Kuo, Bruce S Sachais, Ann H Rux, Yasmina Bdeir, Andrew Mazar, Abd Al-Roof Higazi, and Douglas B Cines* Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA Attenoun, LLC, San Diego, CA, USA Department of Clinical Biochemistry, Hadassah Medical Organization, Jerusalem, Israel * Corresponding author; email: dcines{at}mail.med.upenn.edu. The structural basis of the interaction between single chain urokinase-type plasminogen activator (scuPA) and its receptor (uPAR) is incompletely defined. Several observations indicated the kringle facilitates the binding of uPA to uPAR. A scuPA variant lacking the kringle (K-scuPA) bound to soluble uPAR (suPAR) with the similar "on-rate" but with a faster "off-rate" than wildtype (WT)-scuPA. Binding of K-scuPA, but not WT-scuPA, to suPAR was comparably inhibited by its growth factor domain (GFD) and aminoterminal fragment (ATF). ATF and WT-scuPA, but not GFD, scuPA lacking the GFD (GFD-scuPA), or K-scuPA reconstituted the isolated domains of uPAR. ATF completely inhibited the enzymatic activity of WT-scuPA/suPAR unlike comparable concentrations of GFD. Variants containing mutations that alter the charge, length, or flexibility of linker sequence (residues 43 - 49) between the GFD and the kringle displayed a lower affinity for uPAR, were unable to reconstitute uPAR domains, and their binding to uPAR was inhibited by GFD in the same manner as K-scuPA. A scuPA variant in which the charged amino acids in heparin binding site in the kringle domain were mutated to alanines behaved like K-scuPA, indicating that that the structure of the kringle, as well as its interaction with the GFD, govern receptor binding. These data demonstrate an important role for the kringle in stabilizing the binding of scuPA for uPAR. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Shetty, J. Padijnayayveetil, T. Tucker, D. Stankowska, and S. Idell The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability Am J Physiol Lung Cell Mol Physiol, December 1, 2008; 295(6): L967 - L975. [Abstract] [Full Text] [PDF] V. Stepanova, T. Lebedeva, A. Kuo, S. Yarovoi, S. Tkachuk, S. Zaitsev, K. Bdeir, I. Dumler, M. S. Marks, Y. Parfyonova, et al. Nuclear translocation of urokinase-type plasminogen activator Blood, July 1, 2008; 112(1): 100 - 110. [Abstract] [Full Text] [PDF] P. Begin, K. Tremblay, D. Daley, M. Lemire, S. Claveau, C. Salesse, S. Kacel, A. Montpetit, A. Becker, M. Chan-Yeung, et al. Association of Urokinase-type Plasminogen Activator with Asthma and Atopy Am. J. Respir. 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