Abstract

The goals of the present proposal are to elucidate the molecular mechanisms involved in the interaction of FXI/FXIa with protein and cell surface ligands that are involved in its (XI) activation, and with the plasma protein and cell surface ligands that are involved in the expression and regulation of its (XIa) enzymatic activity. Specifically, the applicant proposes to further fine map: (1) the regions (A45-S86) in the Apple 1 (A1) domain of factor XI involved in its interaction with the cofactor HMWK; (2) the regions (A317-G350) in the apple 4 (A4) domain of factor XI involved in its interaction with the enzyme factor XIIa; (3) the regions (P229-R266) in the apple 3 (A3) domain of factor XI involved in its interaction with the platelet binding site, and (4) the regions (A134- L172) in the apple 2 (A2) domain of factor XI involved in its interaction with the substrate factor IX. Another goal of the application is to understand the structural and functional basis and the physiological relevance of FXI activation by thrombin.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL046213-05
Application #
2222738
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1991-09-30
Project End
1999-08-31
Budget Start
1995-09-01
Budget End
1996-08-31
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost

  Institution

Name
Temple University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122

  Publications

Navaneetham, Duraiswamy; Wu, Wenman; Li, Hongbo et al. (2013) P1 and P2' site mutations convert protease nexin-2 from a factor XIa inhibitor to a plasmin inhibitor. J Biochem 153:221-31
Marcinkiewicz, Mariola M; Sinha, Dipali; Walsh, Peter N (2012) Productive recognition of factor IX by factor XIa exosites requires disulfide linkage between heavy and light chains of factor XIa. J Biol Chem 287:6187-95
Wu, Wenman; Li, Hongbo; Navaneetham, Duraiswamy et al. (2012) The kunitz protease inhibitor domain of protease nexin-2 inhibits factor XIa and murine carotid artery and middle cerebral artery thrombosis. Blood 120:671-7
Su, Ya-Chi; Miller, Tara N; Navaneetham, Duraiswamy et al. (2011) The role of factor XIa (FXIa) catalytic domain exosite residues in substrate catalysis and inhibition by the Kunitz protease inhibitor domain of protease nexin 2. J Biol Chem 286:31904-14
Navaneetham, Duraiswamy; Sinha, Dipali; Walsh, Peter N (2010) Mechanisms and specificity of factor XIa and trypsin inhibition by protease nexin 2 and basic pancreatic trypsin inhibitor. J Biochem 148:467-79
Salameh, Moh'd A; Soares, Alexei S; Navaneetham, Duraiswamy et al. (2010) Determinants of affinity and proteolytic stability in interactions of Kunitz family protease inhibitors with mesotrypsin. J Biol Chem 285:36884-96
Salameh, Moh'd A; Robinson, Jessica L; Navaneetham, Duraiswamy et al. (2010) The amyloid precursor protein/protease nexin 2 Kunitz inhibitor domain is a highly specific substrate of mesotrypsin. J Biol Chem 285:1939-49
Kravtsov, Dmitri V; Matafonov, Anton; Tucker, Erik I et al. (2009) Factor XI contributes to thrombin generation in the absence of factor XII. Blood 114:452-8
Wu, Wenman; Sinha, Dipali; Shikov, Sergei et al. (2008) Factor XI homodimer structure is essential for normal proteolytic activation by factor XIIa, thrombin, and factor XIa. J Biol Chem 283:18655-64
Miller, Tara N; Sinha, Dipali; Baird, T Regan et al. (2007) A catalytic domain exosite (Cys527-Cys542) in factor XIa mediates binding to a site on activated platelets. Biochemistry 46:14450-60

Showing the most recent 10 out of 78 publications