Abstract

The basis for the association between Mac-1 and complement receptor type three (CR3) function will be investigated. The hypothesis that Mac-1 is the CR3 will be tested by determining whether purified Mac-1 can interact with C3bi-coated particles. Further MAb binding to different topographic regions and extracellular and intracellular domains of Mac-1 will be prepared. The location of the C3bi binding site will be probed by comparing the inhibitory effect of MAb with their specificity for subunits (alpha or beta) and proteolytic fragments of Mac-1. Binding of Mac-1 fragments to C3bi-coated particles will be tested. Whether Mac-1 is a receptor which is recycled will be investigated. The steady state ratio of extracellular/intracellular Mac-1 will be determined. Changes in Mac-1 structure of modification occurring after ligand binding will be examined. The orientation and arrangement of Mac-1 in the membrane, and the size of intracellular, extracellular, and intramembranous domains will be investigated. The location of proteolytic fragments will be determined by vectorial labeling and reactivity with MAb to different topographic regions and extracellular and intracellular domains. The structural basis of the homology between Mac-1 and LFA-1, an antigen associated with T lymphoctye-mediated killing, will be further investigated. Mac-1 will be purified and fragments subjected to amino acid sequencing. N-terminal sequencing has shown that the alpha subunits are 33% homologous. (CS)

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA031799-07
Application #
3169921
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1981-07-01
Project End
1988-03-31
Budget Start
1987-04-01
Budget End
1988-03-31
Support Year
7
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

Luo, Bing-Hao; Carman, Christopher V; Springer, Timothy A (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619-47
Luo, Bing-Hao; Springer, Timothy A (2006) Integrin structures and conformational signaling. Curr Opin Cell Biol 18:579-86
Springer, Timothy A (2006) Complement and the multifaceted functions of VWA and integrin I domains. Structure 14:1611-6
Vorup-Jensen, Thomas; Carman, Christopher V; Shimaoka, Motomu et al. (2005) Exposure of acidic residues as a danger signal for recognition of fibrinogen and other macromolecules by integrin alphaXbeta2. Proc Natl Acad Sci U S A 102:1614-9
Vorup-Jensen, Thomas; Ostermeier, Christian; Shimaoka, Motomu et al. (2003) Structure and allosteric regulation of the alpha X beta 2 integrin I domain. Proc Natl Acad Sci U S A 100:1873-8
Springer, Timothy A (2002) Predicted and experimental structures of integrins and beta-propellers. Curr Opin Struct Biol 12:802-13
Takagi, Junichi; Springer, Timothy A (2002) Integrin activation and structural rearrangement. Immunol Rev 186:141-63
Shimaoka, Motomu; Takagi, Junichi; Springer, Timothy A (2002) Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct 31:485-516
Shimaoka, Motomu; Lu, Chafen; Salas, Azucena et al. (2002) Stabilizing the integrin alpha M inserted domain in alternative conformations with a range of engineered disulfide bonds. Proc Natl Acad Sci U S A 99:16737-41
Zang, Q; Springer, T A (2001) Amino acid residues in the PSI domain and cysteine-rich repeats of the integrin beta2 subunit that restrain activation of the integrin alpha(X)beta(2). J Biol Chem 276:6922-9

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