Targeting gC1qR Domains for Therapy Against Infection and Inflammation

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.

Analysis of the Interaction between Globular Head Modules of Human C1q and Its Candidate Receptor gC1qR

“…We could also observe colocalization of individual gh with gC1qR. Although C1q has been shown to bind to residues 76–93 of gC1qR, it appears that there could be additional binding sites on gC1qR (50) involving residues 144–162. This paper together with the other studies, establishing the importance of C1q–gC1qR interaction in disease models, where complement activation is a critical factor in disease progression such as atherosclerosis and Alzheimer’s disease, could be relevant for the development of novel therapeutic strategies.…”

Soluble gC1qR Is an Autocrine Signal That Induces B1R Expression on Endothelial Cells

“…Most proliferating cells, such as cancer, inflammatory, or activated cells, are known to overexpress, as well as secrete, gC1qR into the pericellular milieu, where it can potentially modulate a diverse range of physiological and immunological functions, including angiogenesis (26), vascular permeability (9,27), and inflammation (27), through activation of the complement system and KKS. This is due, in part, to the susceptibility of gC1qR to proteolytic cleavage by enzymes in plasma or membrane-associated enzymes, such as MT1-MMP, as shown earlier (28).…”

Treatment with p33 Curtails Morbidity and Mortality in a Histone-Induced Murine Shock Model

“…Later, it was found that the protein also interacts with other plasma proteins including vitronectin, high-molecular-weight kininogen and the coagulation factors XII and thrombin [28]. In addition to these ligands, a number of bacterial and viral proteins have been identified that can bind either to surface-bound or intracellular p33 [28].…”

“…In addition to these ligands, a number of bacterial and viral proteins have been identified that can bind either to surface-bound or intracellular p33 [28]. While the interactions of bacterial proteins with membrane-attached p33 is thought to promote cell adhesion and internalization of the pathogen [29,30,31], the interaction with viral proteins mainly takes place intracellularly and, in some cases, this has been shown to suppress virus replication [28]. Recently, we reported that p33 exhibits a high affinity for another group of proteins/peptides, namely AMPs.…”