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Targeting gC1qR Domains for Therapy Against Infection and Inflammation

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Complement Therapeutics

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 735))

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 C1q-induced or microbial-ligand-induced inflammatory responses. Employing synthetic peptides and gC1qR 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 (residues190–202), 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 αA coiled-coil N-terminal segment, most of the identified residues form part of the highly charged loops connecting the various β-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.

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Abbreviations

gC1qR:

Receptor for the globular heads of C1q

cC1qR:

Receptor for the collagen tail of C1q

HK:

High molecular weight kininogen

KKS:

Kallikrein–kinin system

BK:

Bradykinin

ATIII:

Antithrombin III

VN:

Vitronectin

TAT:

Thrombin–antithrombin complex

VNTAT:

Vitronectin–thrombin–antithrombin complex

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Acknowledgement

This work was supported in part by grants from the National Institutes of Health (R01 AI 060866 and R01 AI-084178).

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Authors and Affiliations

  1. 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, Jolyon Jesty, Rama Vinayagasundaram, Uma Vinayagasundaram, Yan Ji, Alisa Valentino, Nithin Tumma & Kinga H. Hosszu

  2. The Department of Laboratory Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, 10065, USA

    Ellinor I. B. Peerschke

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  1. Berhane Ghebrehiwet
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  2. Jolyon Jesty
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  3. Rama Vinayagasundaram
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  4. Uma Vinayagasundaram
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  5. Yan Ji
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  6. Alisa Valentino
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  8. Kinga H. Hosszu
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  9. Ellinor I. B. Peerschke
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Correspondence to Berhane Ghebrehiwet .

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Editors and Affiliations

  1. Medicine, University Of Pennsylvania Department Of Pathology Laboratory Of, Philadelphia, Pennsylvania, USA

    John D. Lambris

  2. University of Colorado School of Medicin, Aurora, Colorado, USA

    V. Michael Holers

  3. Department of Pathology & Laboratory Med, University of Pennsylvania School of Med, Philadelphia, Pennsylvania, USA

    Daniel Ricklin

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Ghebrehiwet, B. et al. (2013). Targeting gC1qR Domains for Therapy Against Infection and Inflammation. In: Lambris, J., Holers, V., Ricklin, D. (eds) Complement Therapeutics. Advances in Experimental Medicine and Biology, vol 735. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4118-2_6

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