3t4a

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Structure of a truncated form of Staphylococcal Complement Inhibitor B bound to human C3c at 3.4 Angstrom resolution

Structural highlights

3t4a is a 8 chain structure with sequence from Homo sapiens and Staphylococcus aureus subsp. aureus Mu50. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 3.4Å
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

To survive in immune-competent hosts, the pathogen Staphylococcus aureus expresses and secretes a sophisticated array of proteins that inhibit the complement system. Among these are the staphylococcal complement inhibitors (SCIN), which are composed of three active proteins (SCIN-A, -B, and -C) and one purportedly inactive member (SCIN-D or ORF-D). Because previous work has focused almost exclusively on SCIN-A, we sought to provide initial structure/function information on additional SCIN proteins. To this end we determined crystal structures of an active, N-terminal truncation mutant of SCIN-B (denoted SCIN-B(18-85)) both free and bound to the C3c fragment of complement component C3 at 1.5 and 3.4 A resolution, respectively. Comparison of the C3c/SCIN-B(18-85) structure with that of C3c/SCIN-A revealed that both proteins target the same functional hotspot on the C3b/C3c surface yet harbor diversity in both the type of residues and interactions formed at their C3b/C3c interfaces. Most importantly, these structures allowed identification of Arg(44) and Tyr(51) as residues key for SCIN-B binding to C3b and subsequent inhibition of the AP C3 convertase. In addition, we also solved several crystal structures of SCIN-D to 1.3 A limiting resolution. This revealed an unexpected structural deviation in the N-terminal alpha helix relative to SCIN-A and SCIN-B. Comparative analysis of both electrostatic potentials and surface complementarity suggest a physical explanation for the inability of SCIN-D to bind C3b/C3c. Together, these studies provide a more thorough understanding of immune evasion by S. aureus and enhance potential use of SCIN proteins as templates for design of complement targeted therapeutics.

Diversity in the C3b Convertase Contact Residues and Tertiary Structures of the Staphylococcal Complement Inhibitor (SCIN) Protein Family.,Garcia BL, Summers BJ, Lin Z, Ramyar KX, Ricklin D, Kamath DV, Fu ZQ, Lambris JD, Geisbrecht BV J Biol Chem. 2012 Jan 2;287(1):628-40. Epub 2011 Nov 15. PMID:22086928[36]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ 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
  9. ↑ 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
  10. ↑ 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
  11. ↑ 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
  12. ↑ 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
  13. ↑ 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
  14. ↑ 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
  15. ↑ 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
  16. ↑ 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
  17. ↑ 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
  18. ↑ 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
  19. ↑ 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
  20. ↑ 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
  21. ↑ 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
  22. ↑ 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
  23. ↑ 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
  24. ↑ 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
  25. ↑ 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
  26. ↑ 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
  27. ↑ 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
  28. ↑ 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
  29. ↑ 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
  30. ↑ 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
  31. ↑ 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
  32. ↑ 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
  33. ↑ 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
  34. ↑ 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
  35. ↑ 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
  36. ↑ Garcia BL, Summers BJ, Lin Z, Ramyar KX, Ricklin D, Kamath DV, Fu ZQ, Lambris JD, Geisbrecht BV. Diversity in the C3b Convertase Contact Residues and Tertiary Structures of the Staphylococcal Complement Inhibitor (SCIN) Protein Family. J Biol Chem. 2012 Jan 2;287(1):628-40. Epub 2011 Nov 15. PMID:22086928 doi:10.1074/jbc.M111.298984

Contents


PDB ID 3t4a

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