Factor XIII, the last enzyme activated in the coagulation cascade, stabilizes blood clots by producing covalent crosslinks between fibrin subunits. Defects in factor XIII lead to severe clotting disorders. Its exact roles in biomedical fields such as atherosclerosis, inflammatory bowel disease, and wound healing are not well understood, but factor XIII's localization in non-clotting environment indicates its activity is important in these areas as well. Factor XIII is a member of the transglutaminase class of enzymes which catalyze the formation of covalent bonds between glutamine and lysine residues. To better understand the function of this enzyme, a series of functional and X-ray crystallographic structural studies will be carried out for inhibited complexes of factor XIII, a truncated form of the enzyme that will be easily activated, and several site-directed mutants of the recombinant protein. These studies will determine which amino acids in the protein are important for substrate recognition and enzymatic activity. Structure/function studies of factor XIII are of practical biomedical importance, largely due to factor XIII's role in clotting. As coagulation is worked out in more and more molecular detail, opportunities for the design of structure-specific therapeutic agents for specific clotting enzymes will arise. Factor XIII's role in other biological processes complicates it potential for structure-based drug design. However, the studies proposed here are likely to identify suitably specific drug-design targets that can be used to control thrombosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL050355-05
Application #
2685406
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1994-04-01
Project End
2000-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Washington
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195