Abstract

This is a proposal to determine and study the three- dimensional structure of the A1 domain of human von Willebrand (vWF) factor. The A1 domain is responsible for binding the platelet glycoprotein GPlb receptor complex and thereby activating platelet aggregation. Binding to native vWF only occurs under high shear conditions or when the factor is absorbed to surfaces, but the isolated At domain binds GPlb in the solution phase. Certain heritable forms of von Willebrand's disease map as single substitution mutations within the A1 domain. Thus, the structure of this domain will shed light on a number of important biological and pathological functions of this molecule.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL055375-02
Application #
2029626
Study Section
Biophysical Chemistry Study Section (BBCB)
Project Start
1996-01-01
Project End
1998-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Peterson, Eric C; Celikel, Reha; Gokulan, Kuppan et al. (2013) Structural characterization of a therapeutic anti-methamphetamine antibody fragment: oligomerization and binding of active metabolites. PLoS One 8:e82690
Zarpellon, Alessandro; Celikel, Reha; Roberts, James R et al. (2011) Binding of alpha-thrombin to surface-anchored platelet glycoprotein Ib(alpha) sulfotyrosines through a two-site mechanism involving exosite I. Proc Natl Acad Sci U S A 108:8628-33
Celikel, Reha; Peterson, Eric C; Owens, S Michael et al. (2009) Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse-Methamphetamine and 3,4-methylenedioxymethamphetamine. Protein Sci 18:2336-45
Vasudevan, Sona; Celikel, Reha; Ruggeri, Zaverio M et al. (2004) A single amino acid change in the binding pocket alters specificity of an anti-integrin antibody AP7.4 as revealed by its crystal structure. Blood Cells Mol Dis 32:176-81
Corrons, Joan-Lluis Vives; Garcia, Estefania; Tusell, Joan J et al. (2003) Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G>A, 190G>A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia. Blood 102:353-6
Celikel, Reha; McClintock, Richard A; Roberts, James R et al. (2003) Modulation of alpha-thrombin function by distinct interactions with platelet glycoprotein Ibalpha. Science 301:218-21
Varughese, Kottayil I; Celikel, Reha; Ruggeri, Zaverio M (2002) Structure and function of the von Willebrand factor A1 domain. Curr Protein Pept Sci 3:301-12
Sen, U; Vasudevan, S; Subbarao, G et al. (2001) Crystal structure of the von Willebrand factor modulator botrocetin. Biochemistry 40:345-52
Celikel, R; Madhusudan; Varughese, K I et al. (1997) Crystal structure of NMC-4 fab anti-von Willebrand factor A1 domain. Blood Cells Mol Dis 23:123-34
Balakrishnan, R; Ramasubbu, N; Varughese, K I et al. (1997) Crystal structures of the copper and nickel complexes of RNase A: metal-induced interprotein interactions and identification of a novel copper binding motif. Proc Natl Acad Sci U S A 94:9620-5