| Structural highlights
Function
C1QBP_HUMAN Is believed to be a multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing. At the cell surface is thought to act as an endothelial receptor for plasma proteins of the complement and kallikrein-kinin cascades. Putative receptor for C1q; specifically binds to the globular "heads" of C1q thus inhibiting C1; may perform the receptor function through a complex with C1qR/CD93. In complex with cytokeratin-1/KRT1 is a high affinty receptor for kininogen-1/HMWK. Can also bind other plasma proteins, such as coagulation factor XII leading to its autoactivation. May function to bind initially fluid kininogen-1 to the cell membrane. The secreted form may enhance both extrinsic and intrinsic coagulation pathways. It is postulated that the cell surface form requires docking with transmembrane proteins for downstream signaling which might be specific for a cell-type or response. By acting as C1q receptor is involved in chemotaxis of immature dendritic cells and neutrophils and is proposed to signal through CD209/DC-SIGN on immature dendritic cells, through integrin alpha-4/beta-1 during trophoblast invasion of the decidua, and through integrin beta-1 during endothelial cell adhesion and spreading. Signaling involved in inhibition of innate immune response is implicating the PI3K-AKT/PKB pathway. In mitochondrial translation may be involved in formation of functional 55S mitoribosomes; the function seems to involve its RNA-binding activity. May be involved in the nucleolar ribosome maturation process; the function may involve the exchange of FBL for RRP1 in the association with pre-ribosome particles. Involved in regulation of RNA splicing by inhibiting the RNA-binding capacity of SRSF1 and its phosphorylation. Is required for the nuclear translocation of splicing factor U2AF1L4. Involved in regulation of CDKN2A- and HRK-mediated apoptosis. Stabilizes mitochondrial CDKN2A isoform smARF. May be involved in regulation of FOXC1 transcriptional activity and NFY/CCAAT-binding factor complex-mediated transcription. In infection processes acts as an attachment site for microbial proteins, including Listeria monocytogenes internalin B and Staphylococcus aureus protein A. May play a role in antibacterial defense as it can bind to cell surface hyaluronan and inhibit Streptococcus pneumoniae hyaluronate lyase. Involved in replication of Rubella virus. May be involved in modulation of the immune response; ligation by HCV core protein is resulting in suppresion of interleukin-12 production in monocyte-derived dendritic cells. Involved in regulation of antiviral response by inhibiting DDX58- and IFIH1-mediated signaling pathways probably involving its association with MAVS after viral infection. Involved in HIV-1 replication, presumably by contributing to splicing of viral RNA.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21]
Publication Abstract from PubMed
The protein gC1qR/C1qBP/HABP-1 plays an essential role in mitochondrial biogenesis, but becomes localized at the cellular surface in numerous pathophysiological states. When this occurs on endothelial cells, surface-exposed gC1qR activates the classical pathway of complement. It also promotes assembly of a multi-protein complex comprised of coagulation factor XII (FXII), pre-kallikrein (PK), and high-molecular weight kininogen (HMWK) that activates the contact system and the kinin-generating system. Since surface-exposed gC1qR triggers intravascular inflammatory pathways, there is interest in identifying molecules that block gC1qR function. Here we further that objective by reporting the outcome of a structure/function investigation of gC1qR, its interactions with FXII, and the impact of a panel of monoclonal anti-gC1qR antibodies on FXII binding to gC1qR. Although deletion mutants have been used extensively to assess gC1qR function, none of these proteins have been characterized structurally. To that end, we determined a 2.2 A resolution crystal structure of a gC1qR mutant lacking both of its acidic loops, but which retained nanomolar-affinity binding to FXII and FXIIa. This structure revealed that the trimeric gC1qR assembly was maintained despite loss of roughly thirty residues. Characterization of a novel panel of anti-gC1qR monoclonal antibodies identified several with biochemical properties distinct from previously described antibodies, as well as one which bound to the first acidic loop of gC1qR. Intriguingly, we found that each of these antibodies could partly inhibit binding of FXII and FXIIa to gC1qR. Based on these results and previously published studies, we offer new perspectives for developing gC1qR inhibitors.
gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII.,Zhang Y, Vontz AJ, Kallenberger EM, Xu X, Ploscariu NT, Ramyar KX, Garcia BL, Ghebrehiwet B, Geisbrecht BV Front Immunol. 2022 Jul 5;13:887742. doi: 10.3389/fimmu.2022.887742. eCollection , 2022. PMID:35865516[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Joseph K, Ghebrehiwet B, Peerschke EI, Reid KB, Kaplan AP. Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular "heads" of C1q (gC1q-R). Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8552-7. PMID:8710908
- ↑ Leigh LE, Ghebrehiwet B, Perera TP, Bird IN, Strong P, Kishore U, Reid KB, Eggleton P. C1q-mediated chemotaxis by human neutrophils: involvement of gClqR and G-protein signalling mechanisms. Biochem J. 1998 Feb 15;330 ( Pt 1):247-54. PMID:9461517
- ↑ Joseph K, Ghebrehiwet B, Kaplan AP. Cytokeratin 1 and gC1qR mediate high molecular weight kininogen binding to endothelial cells. Clin Immunol. 1999 Sep;92(3):246-55. PMID:10479529 doi:10.1006/clim.1999.4753
- ↑ Petersen-Mahrt SK, Estmer C, Ohrmalm C, Matthews DA, Russell WC, Akusjarvi G. The splicing factor-associated protein, p32, regulates RNA splicing by inhibiting ASF/SF2 RNA binding and phosphorylation. EMBO J. 1999 Feb 15;18(4):1014-24. PMID:10022843 doi:10.1093/emboj/18.4.1014
- ↑ Braun L, Ghebrehiwet B, Cossart P. gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes. EMBO J. 2000 Apr 3;19(7):1458-66. PMID:10747014 doi:10.1093/emboj/19.7.1458
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- ↑ Zheng YH, Yu HF, Peterlin BM. Human p32 protein relieves a post-transcriptional block to HIV replication in murine cells. Nat Cell Biol. 2003 Jul;5(7):611-8. PMID:12833064 doi:10.1038/ncb1000
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- ↑ Waggoner SN, Cruise MW, Kassel R, Hahn YS. gC1q receptor ligation selectively down-regulates human IL-12 production through activation of the phosphoinositide 3-kinase pathway. J Immunol. 2005 Oct 1;175(7):4706-14. PMID:16177118
- ↑ Vegh Z, Kew RR, Gruber BL, Ghebrehiwet B. Chemotaxis of human monocyte-derived dendritic cells to complement component C1q is mediated by the receptors gC1qR and cC1qR. Mol Immunol. 2006 Mar;43(9):1402-7. Epub 2005 Sep 2. PMID:16140380 doi:10.1016/j.molimm.2005.07.030
- ↑ Waggoner SN, Hall CH, Hahn YS. HCV core protein interaction with gC1q receptor inhibits Th1 differentiation of CD4+ T cells via suppression of dendritic cell IL-12 production. J Leukoc Biol. 2007 Dec;82(6):1407-19. Epub 2007 Sep 19. PMID:17881511 doi:10.1189/jlb.0507268
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- ↑ Yadav G, Prasad RL, Jha BK, Rai V, Bhakuni V, Datta K. Evidence for inhibitory interaction of hyaluronan-binding protein 1 (HABP1/p32/gC1qR) with Streptococcus pneumoniae hyaluronidase. J Biol Chem. 2009 Feb 6;284(6):3897-905. doi: 10.1074/jbc.M804246200. Epub 2008, Nov 11. PMID:19004836 doi:10.1074/jbc.M804246200
- ↑ Xu L, Xiao N, Liu F, Ren H, Gu J. Inhibition of RIG-I and MDA5-dependent antiviral response by gC1qR at mitochondria. Proc Natl Acad Sci U S A. 2009 Feb 3;106(5):1530-5. doi: 10.1073/pnas.0811029106., Epub 2009 Jan 21. PMID:19164550 doi:10.1073/pnas.0811029106
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- ↑ Yoshikawa H, Komatsu W, Hayano T, Miura Y, Homma K, Izumikawa K, Ishikawa H, Miyazawa N, Tachikawa H, Yamauchi Y, Isobe T, Takahashi N. Splicing factor 2-associated protein p32 participates in ribosome biogenesis by regulating the binding of Nop52 and fibrillarin to preribosome particles. Mol Cell Proteomics. 2011 Aug;10(8):M110.006148. doi: 10.1074/mcp.M110.006148., Epub 2011 May 2. PMID:21536856 doi:10.1074/mcp.M110.006148
- ↑ Pixley RA, Espinola RG, Ghebrehiwet B, Joseph K, Kao A, Bdeir K, Cines DB, Colman RW. Interaction of high-molecular-weight kininogen with endothelial cell binding proteins suPAR, gC1qR and cytokeratin 1 determined by surface plasmon resonance (BiaCore). Thromb Haemost. 2011 Jun;105(6):1053-9. doi: 10.1160/TH10-09-0591. Epub 2011 May , 5. PMID:21544310 doi:10.1160/TH10-09-0591
- ↑ Hosszu KK, Valentino A, Vinayagasundaram U, Vinayagasundaram R, Joyce MG, Ji Y, Peerschke EI, Ghebrehiwet B. DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells. Blood. 2012 Aug 9;120(6):1228-36. doi: 10.1182/blood-2011-07-369728. Epub 2012, Jun 13. PMID:22700724 doi:10.1182/blood-2011-07-369728
- ↑ Zhang Y, Vontz AJ, Kallenberger EM, Xu X, Ploscariu NT, Ramyar KX, Garcia BL, Ghebrehiwet B, Geisbrecht BV. gC1qR/C1qBP/HABP-1: Structural Analysis of the Trimeric Core Region, Interactions With a Novel Panel of Monoclonal Antibodies, and Their Influence on Binding to FXII. Front Immunol. 2022 Jul 5;13:887742. doi: 10.3389/fimmu.2022.887742. eCollection , 2022. PMID:35865516 doi:http://dx.doi.org/10.3389/fimmu.2022.887742
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