| Structural highlights
2xwb is a 8 chain structure with sequence from Homo sapiens and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , |
| Related: | 1dfp, 1dic, 2xw9, 1dle, 1rrk, 2xqw, 1rs0, 2wii, 1bio, 1dsu, 1hfd, 2a74, 1ghq, 2hr0, 2win, 1dst, 2a73, 1q0p, 2wy7, 2xwa, 1w2s, 1c3d, 2xwj, 1fdp, 1rtk, 2wy8 |
| Activity: | Alternative-complement-pathway C3/C5 convertase, with EC number 3.4.21.47 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
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Disease
[CFAD_HUMAN] Defects in CFD are the cause of complement factor D deficiency (CFDD) [MIM:613912]. CFDD is an immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway. [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] [CFAB_HUMAN] Defects in CFB are a cause of susceptibility to hemolytic uremic syndrome atypical type 4 (AHUS4) [MIM:612924]. 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.[12] [13]
Function
[CFAD_HUMAN] Factor D cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. Its function is homologous to that of C1s in the classical pathway. [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.[14] [15] [16] [17] [18] [19] [20] [21] 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.[22] [23] [24] [25] [26] [27] [28] [29] 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.[30] [31] [32] [33] [34] [35] [36] [37] [CFAB_HUMAN] Factor B which is part of the alternate pathway of the complement system is cleaved by factor D into 2 fragments: Ba and Bb. Bb, a serine protease, then combines with complement factor 3b to generate the C3 or C5 convertase. It has also been implicated in proliferation and differentiation of preactivated B-lymphocytes, rapid spreading of peripheral blood monocytes, stimulation of lymphocyte blastogenesis and lysis of erythrocytes. Ba inhibits the proliferation of preactivated B-lymphocytes.
Publication Abstract from PubMed
Activation of the complement cascade induces inflammatory responses and marks cells for immune clearance. In the central complement-amplification step, a complex consisting of surface-bound C3b and factor B is cleaved by factor D to generate active convertases on targeted surfaces. We present crystal structures of the pro-convertase C3bB at 4 angstrom resolution and its complex with factor D at 3.5 angstrom resolution. Our data show how factor B binding to C3b forms an open "activation" state of C3bB. Factor D specifically binds the open conformation of factor B through a site distant from the catalytic center and is activated by the substrate, which displaces factor D's self-inhibitory loop. This concerted proteolytic mechanism, which is cofactor-dependent and substrate-induced, restricts complement amplification to C3b-tagged target cells.
Structures of C3b in complex with factors B and D give insight into complement convertase formation.,Forneris F, Ricklin D, Wu J, Tzekou A, Wallace RS, Lambris JD, Gros P Science. 2010 Dec 24;330(6012):1816-20. PMID:21205667[38]
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
- ↑ Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2007 Jan 2;104(1):240-5. Epub 2006 Dec 20. PMID:17182750 doi:10.1073/pnas.0603420103
- ↑ 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
- ↑ 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
- ↑ Forneris F, Ricklin D, Wu J, Tzekou A, Wallace RS, Lambris JD, Gros P. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science. 2010 Dec 24;330(6012):1816-20. PMID:21205667 doi:10.1126/science.1195821
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