title: Targeting gC1qR domains for therapy against infection and inflammation.
abstract: Abstract The receptor for the globular heads of C1q, gC1qR/p33, is a widely expressed cellular protein, which binds to diverse ligands including plasma proteins, cellular proteins, and microbial ligands. In addition to C1q, gC1qR also binds high molecular weight kininogen (HK), which also has two other cell surface sites, namely, cytokeratin 1 and urokinase plasminogen activator receptor (uPAR). On endothelial cells (ECs), the three molecules form two closely associated bimolecular complexes of gC1qR/cytokeratin 1 and uPAR/cytokeratin 1. However, by virtue of its high affinity for HK, gC1qR plays a central role in the assembly of the kallikrein-kinin system, leading to the generation of bradykinin (BK). BK in turn is largely responsible for the vascular leakage and associated inflammation seen in angioedema patients. Therefore, blockade of gC1qR by inhibitory peptides or antibodies may not only prevent the generation of BK but also reduce Clq-induced or microbial-ligand-induced inflammatory responses. Employing synthetic peptides and gClqR deletion mutants, we confirmed previously predicted sites for C1q (residues 75-96) and HK (residues 204-218) and identified additional sites for both C1q and HK (residues 190-202), for C1q (residues 144-162), and for HIV-1 gp41 (residues 174-180). With the exception of residues 75-96, which is located in the alphaA coiled-coil N-terminal segment, most of the identified residues form part of the highly charged loops connecting the various beta-strands in the crystal structure. Taken together, the data support the notion that gC1qR could serve as a novel molecular target for the design of antibody-based and/or peptide-based therapy to attenuate acute and/or chronic inflammation associated with vascular leakage and infection.
authors: The Department of Medicine, Stony Brook University School of Medicine, Health Sciences Center, T-16; Room 040, Stony Brook, New York, NY 11794-8161, USA. Berhane.Ghebrehiwet@stonybrook.edu
authors: Berhane
authors: B
authors: Ghebrehiwet
authors: Jolyon
authors: J
authors: Jesty
authors: Rama
authors: R
authors: Vinayagasundaram
authors: Uma
authors: U
authors: Vinayagasundaram
authors: Yan
authors: Y
authors: Ji
authors: Alisa
authors: A
authors: Valentino
authors: Nithin
authors: N
authors: Tumma
authors: Kinga H
authors: KH
authors: Hosszu
authors: Ellinor I B
authors: EI
authors: Peerschke
mesh_terms: D000818:Animals; D015922:Complement C1q / Q000187:drug effects*; D006801:Humans; D007239:Infections / Q000188:drug therapy*; D007249:Inflammation / Q000188:drug therapy*; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy / Q000503:physiopathology; D011951:Receptors, Complement / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics
chemical_list: D008024:Ligands; D011951:Receptors, Complement; D015922:Complement C1q