Human vitronectin is a glycoprotein present in both the circulation and the extracellular matrix (ECM). In both of these locations, it interacts with a wide variety of other macromolecules and provides regulation of many physiological processes. Circulating vitronectin associates with the vascular ECM, and its presence is important in pathological situations or in cancer metastasis and tissue remodeling. The factors that control the binding interactions and determine activities of vitronectin in the circulation as well as in the matrix are important unsolved issues. We have adopted the following as our working hypotheses regarding vitronectin complexes and their activities: Vitronectin is a multi-domain protein with distributed binding sites to control the dynamic processes of coagulation vs. fibrinolysis and binding vs. release from the matrix. Complexes of vitronectin with biological targets (plasminogen activator inhibitor type 1 (PAl-l) or the thrombin-antithrombin (T-AT) pair) associate into higher-order structures with altered functions and tissue compartmentalization. Vitronectin complexes are recognized by ceU-surface receptors, with a preference for higher-order complexes over free, monomeric vitronectin. During the last grant period we focused on assembly of complexes between vitronectin and PAl-l, demonstrating association of these complexes into higher-order species that bind preferentially to the ECM and exhibit altered receptor-binding interactions. In the next period, we will expand our focus to other relevant biological complexes to provide mechanistic and structural explanations for the function of vitronectin in the circulation and in the ECM. We will: 1. Investigate the mechanism for changes in matrix- and receptor-binding functions of higher-order PAl-1/vitronectin complexes, 2. Pursue the three-dimensional structure of the N-terminal somatomedin B domain that contains sites for binding to PAl-1 and integrins, and 3. Characterize the interaction of vitronectin and the T-AT pair.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050676-12
Application #
7065138
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Hasan, Ahmed AK
Project Start
1993-08-01
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2008-05-31
Support Year
12
Fiscal Year
2006
Total Cost
$247,788
Indirect Cost
Name
University of Tennessee Knoxville
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
003387891
City
Knoxville
State
TN
Country
United States
Zip Code
37996