| Structural highlights
Disease
CO3_HUMAN Defects in C3 are the cause of complement component 3 deficiency (C3D) [MIM:613779. A rare defect of the complement classical pathway. Patients develop recurrent, severe, pyogenic infections because of ineffective opsonization of pathogens. Some patients may also develop autoimmune disorders, such as arthralgia and vasculitic rashes, lupus-like syndrome and membranoproliferative glomerulonephritis.[1] [2] [3] [4] [5] [:] Genetic variation in C3 is associated with susceptibility to age-related macular degeneration type 9 (ARMD9) [MIM:611378. ARMD is a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane.[6] [7] Defects in C3 are a cause of susceptibility to hemolytic uremic syndrome atypical type 5 (AHUS5) [MIM:612925. An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Note=Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype.[8] [9] [10] Note=Increased levels of C3 and its cleavage product ASP, are associated with obesity, diabetes and coronary heart disease. Short-term endurance training reduces baseline ASP levels and subsequently fat storage.[11]
Function
CO3_HUMAN C3 plays a central role in the activation of the complement system. Its processing by C3 convertase is the central reaction in both classical and alternative complement pathways. After activation C3b can bind covalently, via its reactive thioester, to cell surface carbohydrates or immune aggregates.[12] [13] [14] [15] [16] [17] [18] [19] Derived from proteolytic degradation of complement C3, C3a anaphylatoxin is a mediator of local inflammatory process. It induces the contraction of smooth muscle, increases vascular permeability and causes histamine release from mast cells and basophilic leukocytes.[20] [21] [22] [23] [24] [25] [26] [27] Acylation stimulating protein (ASP): adipogenic hormone that stimulates triglyceride (TG) synthesis and glucose transport in adipocytes, regulating fat storage and playing a role in postprandial TG clearance. Appears to stimulate TG synthesis via activation of the PLC, MAPK and AKT signaling pathways. Ligand for GPR77. Promotes the phosphorylation, ARRB2-mediated internalization and recycling of GPR77.[28] [29] [30] [31] [32] [33] [34] [35]
Publication Abstract from PubMed
Complement receptor 3 (CR3, also known as Mac-1, integrin alpha(M)beta(2), or CD11b/CD18) is expressed on a subset of myeloid and certain activated lymphoid cells. CR3 is essential for the phagocytosis of complement-opsonized particles such as pathogens and apoptotic or necrotic cells opsonized with the complement fragment iC3b and, to a lesser extent, C3dg. Although the interaction between the iC3b thioester domain and the ligand binding CR3 alpha(M) I-domain is structurally and functionally well characterized, the nature of additional CR3-iC3b interactions required for phagocytosis of complement-opsonized objects remains obscure. In this study, we analyzed the interaction between iC3b and the 150-kDa headpiece fragment of the CR3 ectodomain. Surface plasmon resonance experiments demonstrated a 30 nM affinity of the CR3 headpiece for iC3b compared with 515 nM for the iC3b thioester domain, whereas experiments monitoring binding of iC3b to CR3-expressing cells suggested an affinity of 50 nM for the CR3-iC3b interaction. Small angle x-ray scattering analysis revealed that iC3b adopts an extended but preferred conformation in solution. Upon interaction with CR3, iC3b rearranges to form a compact receptor-ligand complex. Overall, the data suggest that the iC3b-CR3 interaction is of high affinity and relies on minor contacts formed between CR3 and regions outside the iC3b thioester domain. Our results rationalize the more efficient phagocytosis elicited by iC3b than by C3dg and pave the way for the development of specific therapeutics for the treatment of inflammatory and neurodegenerative diseases that do not interfere with the recognition of noncomplement CR3 ligands.
Complement Receptor 3 Forms a Compact High-Affinity Complex with iC3b.,Jensen RK, Bajic G, Sen M, Springer TA, Vorup-Jensen T, Andersen GR J Immunol. 2021 Jun 15;206(12):3032-3042. doi: 10.4049/jimmunol.2001208. Epub , 2021 Jun 11. PMID:34117107[36]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Onat A, Hergenc G, Can G, Kaya Z, Yuksel H. Serum complement C3: a determinant of cardiometabolic risk, additive to the metabolic syndrome, in middle-aged population. Metabolism. 2010 May;59(5):628-34. doi: 10.1016/j.metabol.2009.09.006. Epub 2009 , Nov 14. PMID:19913840 doi:10.1016/j.metabol.2009.09.006
- ↑ Nagar B, Jones RG, Diefenbach RJ, Isenman DE, Rini JM. X-ray crystal structure of C3d: a C3 fragment and ligand for complement receptor 2. Science. 1998 May 22;280(5367):1277-81. PMID:9596584
- ↑ Szakonyi G, Guthridge JM, Li D, Young K, Holers VM, Chen XS. Structure of complement receptor 2 in complex with its C3d ligand. Science. 2001 Jun 1;292(5522):1725-8. PMID:11387479 doi:10.1126/science.1059118
- ↑ Gilbert HE, Eaton JT, Hannan JP, Holers VM, Perkins SJ. Solution structure of the complex between CR2 SCR 1-2 and C3d of human complement: an X-ray scattering and sedimentation modelling study. J Mol Biol. 2005 Feb 25;346(3):859-73. Epub 2005 Jan 12. PMID:15713468 doi:10.1016/j.jmb.2004.12.006
- ↑ Singer L, Whitehead WT, Akama H, Katz Y, Fishelson Z, Wetsel RA. Inherited human complement C3 deficiency. An amino acid substitution in the beta-chain (ASP549 to ASN) impairs C3 secretion. J Biol Chem. 1994 Nov 11;269(45):28494-9. PMID:7961791
- ↑ Onat A, Hergenc G, Can G, Kaya Z, Yuksel H. Serum complement C3: a determinant of cardiometabolic risk, additive to the metabolic syndrome, in middle-aged population. Metabolism. 2010 May;59(5):628-34. doi: 10.1016/j.metabol.2009.09.006. Epub 2009 , Nov 14. PMID:19913840 doi:10.1016/j.metabol.2009.09.006
- ↑ Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007 Aug 9;357(6):553-61. Epub 2007 Jul 18. PMID:17634448 doi:NEJMoa072618
- ↑ Onat A, Hergenc G, Can G, Kaya Z, Yuksel H. Serum complement C3: a determinant of cardiometabolic risk, additive to the metabolic syndrome, in middle-aged population. Metabolism. 2010 May;59(5):628-34. doi: 10.1016/j.metabol.2009.09.006. Epub 2009 , Nov 14. PMID:19913840 doi:10.1016/j.metabol.2009.09.006
- ↑ Fremeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, Moghal N, Kaplan BS, Weiss RA, Lhotta K, Kapur G, Mattoo T, Nivet H, Wong W, Gie S, Hurault de Ligny B, Fischbach M, Gupta R, Hauhart R, Meunier V, Loirat C, Dragon-Durey MA, Fridman WH, Janssen BJ, Goodship TH, Atkinson JP. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood. 2008 Dec 15;112(13):4948-52. doi: 10.1182/blood-2008-01-133702. Epub 2008 , Sep 16. PMID:18796626 doi:10.1182/blood-2008-01-133702
- ↑ Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJ. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010 Jun;31(6):E1445-60. doi: 10.1002/humu.21256. PMID:20513133 doi:10.1002/humu.21256
- ↑ Onat A, Hergenc G, Can G, Kaya Z, Yuksel H. Serum complement C3: a determinant of cardiometabolic risk, additive to the metabolic syndrome, in middle-aged population. Metabolism. 2010 May;59(5):628-34. doi: 10.1016/j.metabol.2009.09.006. Epub 2009 , Nov 14. PMID:19913840 doi:10.1016/j.metabol.2009.09.006
- ↑ Baldo A, Sniderman AD, St-Luce S, Avramoglu RK, Maslowska M, Hoang B, Monge JC, Bell A, Mulay S, Cianflone K. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis. J Clin Invest. 1993 Sep;92(3):1543-7. PMID:8376604 doi:http://dx.doi.org/10.1172/JCI116733
- ↑ Cianflone KM, Sniderman AD, Walsh MJ, Vu HT, Gagnon J, Rodriguez MA. Purification and characterization of acylation stimulating protein. J Biol Chem. 1989 Jan 5;264(1):426-30. PMID:2909530
- ↑ Tao Y, Cianflone K, Sniderman AD, Colby-Germinario SP, Germinario RJ. Acylation-stimulating protein (ASP) regulates glucose transport in the rat L6 muscle cell line. Biochim Biophys Acta. 1997 Feb 18;1344(3):221-9. PMID:9059512
- ↑ Saleh J, Summers LK, Cianflone K, Fielding BA, Sniderman AD, Frayn KN. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period. J Lipid Res. 1998 Apr;39(4):884-91. PMID:9555951
- ↑ Murray I, Kohl J, Cianflone K. Acylation-stimulating protein (ASP): structure-function determinants of cell surface binding and triacylglycerol synthetic activity. Biochem J. 1999 Aug 15;342 ( Pt 1):41-8. PMID:10432298
- ↑ Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K. C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem. 2005 Jun 24;280(25):23936-44. Epub 2005 Apr 14. PMID:15833747 doi:10.1074/jbc.M406921200
- ↑ Maslowska M, Legakis H, Assadi F, Cianflone K. Targeting the signaling pathway of acylation stimulating protein. J Lipid Res. 2006 Mar;47(3):643-52. Epub 2005 Dec 6. PMID:16333141 doi:10.1194/jlr.M500500-JLR200
- ↑ Cui W, Simaan M, Laporte S, Lodge R, Cianflone K. C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation. Mol Immunol. 2009 Sep;46(15):3086-98. Epub 2009 Jul 16. PMID:19615750 doi:S0161-5890(09)00421-0
- ↑ Baldo A, Sniderman AD, St-Luce S, Avramoglu RK, Maslowska M, Hoang B, Monge JC, Bell A, Mulay S, Cianflone K. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis. J Clin Invest. 1993 Sep;92(3):1543-7. PMID:8376604 doi:http://dx.doi.org/10.1172/JCI116733
- ↑ Cianflone KM, Sniderman AD, Walsh MJ, Vu HT, Gagnon J, Rodriguez MA. Purification and characterization of acylation stimulating protein. J Biol Chem. 1989 Jan 5;264(1):426-30. PMID:2909530
- ↑ Tao Y, Cianflone K, Sniderman AD, Colby-Germinario SP, Germinario RJ. Acylation-stimulating protein (ASP) regulates glucose transport in the rat L6 muscle cell line. Biochim Biophys Acta. 1997 Feb 18;1344(3):221-9. PMID:9059512
- ↑ Saleh J, Summers LK, Cianflone K, Fielding BA, Sniderman AD, Frayn KN. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period. J Lipid Res. 1998 Apr;39(4):884-91. PMID:9555951
- ↑ Murray I, Kohl J, Cianflone K. Acylation-stimulating protein (ASP): structure-function determinants of cell surface binding and triacylglycerol synthetic activity. Biochem J. 1999 Aug 15;342 ( Pt 1):41-8. PMID:10432298
- ↑ Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K. C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem. 2005 Jun 24;280(25):23936-44. Epub 2005 Apr 14. PMID:15833747 doi:10.1074/jbc.M406921200
- ↑ Maslowska M, Legakis H, Assadi F, Cianflone K. Targeting the signaling pathway of acylation stimulating protein. J Lipid Res. 2006 Mar;47(3):643-52. Epub 2005 Dec 6. PMID:16333141 doi:10.1194/jlr.M500500-JLR200
- ↑ Cui W, Simaan M, Laporte S, Lodge R, Cianflone K. C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation. Mol Immunol. 2009 Sep;46(15):3086-98. Epub 2009 Jul 16. PMID:19615750 doi:S0161-5890(09)00421-0
- ↑ Baldo A, Sniderman AD, St-Luce S, Avramoglu RK, Maslowska M, Hoang B, Monge JC, Bell A, Mulay S, Cianflone K. The adipsin-acylation stimulating protein system and regulation of intracellular triglyceride synthesis. J Clin Invest. 1993 Sep;92(3):1543-7. PMID:8376604 doi:http://dx.doi.org/10.1172/JCI116733
- ↑ Cianflone KM, Sniderman AD, Walsh MJ, Vu HT, Gagnon J, Rodriguez MA. Purification and characterization of acylation stimulating protein. J Biol Chem. 1989 Jan 5;264(1):426-30. PMID:2909530
- ↑ Tao Y, Cianflone K, Sniderman AD, Colby-Germinario SP, Germinario RJ. Acylation-stimulating protein (ASP) regulates glucose transport in the rat L6 muscle cell line. Biochim Biophys Acta. 1997 Feb 18;1344(3):221-9. PMID:9059512
- ↑ Saleh J, Summers LK, Cianflone K, Fielding BA, Sniderman AD, Frayn KN. Coordinated release of acylation stimulating protein (ASP) and triacylglycerol clearance by human adipose tissue in vivo in the postprandial period. J Lipid Res. 1998 Apr;39(4):884-91. PMID:9555951
- ↑ Murray I, Kohl J, Cianflone K. Acylation-stimulating protein (ASP): structure-function determinants of cell surface binding and triacylglycerol synthetic activity. Biochem J. 1999 Aug 15;342 ( Pt 1):41-8. PMID:10432298
- ↑ Kalant D, MacLaren R, Cui W, Samanta R, Monk PN, Laporte SA, Cianflone K. C5L2 is a functional receptor for acylation-stimulating protein. J Biol Chem. 2005 Jun 24;280(25):23936-44. Epub 2005 Apr 14. PMID:15833747 doi:10.1074/jbc.M406921200
- ↑ Maslowska M, Legakis H, Assadi F, Cianflone K. Targeting the signaling pathway of acylation stimulating protein. J Lipid Res. 2006 Mar;47(3):643-52. Epub 2005 Dec 6. PMID:16333141 doi:10.1194/jlr.M500500-JLR200
- ↑ Cui W, Simaan M, Laporte S, Lodge R, Cianflone K. C5a- and ASP-mediated C5L2 activation, endocytosis and recycling are lost in S323I-C5L2 mutation. Mol Immunol. 2009 Sep;46(15):3086-98. Epub 2009 Jul 16. PMID:19615750 doi:S0161-5890(09)00421-0
- ↑ Jensen RK, Bajic G, Sen M, Springer TA, Vorup-Jensen T, Andersen GR. Complement Receptor 3 Forms a Compact High-Affinity Complex with iC3b. J Immunol. 2021 Jun 15;206(12):3032-3042. PMID:34117107 doi:10.4049/jimmunol.2001208
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