期刊
FRONTIERS IN IMMUNOLOGY
卷 2, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2011.00058
关键词
gC1gR; vascular permeability; inflammation; kininogen; bradykinin
类别
资金
- National Institutes of Health [R01 AI 060866, R01 AI-084178]
The endothelial cell receptor complex for kininogen (HK) comprises gC1gR, cytokeratin 1, and urokinase-type plasminogen activator receptor and is essential for activation of the kinin system that leads to bradykinin (BK) generation. Of these, gC1gR/p33 constitutes a high affinity site for HK - the BK precursor - and is therefore critical for the assembly of the kinin-generating cascade. Previous studies have identified a putative HK site within the C-terminal domain (residues 204-218) of gC1gR recognized by mAb 74.5.2. In these studies, we used information from the crystal structure of gC1gR, to engineer several deletion (A) mutants and test their ability to bind and/or support BK generation. While deletion of residues 204-218 (gC1gRA204-218), showed significantly reduced binding to HK, BK generation was not affected when tested by a sensitive bradykinin immunoassay. In fact, all of the gC1gR deletion mutants supported BK generation with the exception of gC1gR Delta 154-162 and a point mutation in which Trp 233 was substituted with Gly. Binding studies also identified the existence of two additional sites at residues 144-162 and 190-202. Moreover, binding of HK to a synthetic peptide 190-202 was inhibited by mAbs 48 and 83, but not by mAb 74.5.2. Since a single residue separates domains 190-202 and 204-218, they may be part of a highly stable HK binding pocket and therefore a potential target for drug design to prevent vascular permeability and inflammation.
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