Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity

Journal of Immunology

Volumn 194, Issue 7, 2015, Pages 3305-3316

  Sfyroera, Georgia ^a   Ricklin, Daniel ^a   Reis, Edimara S ^a   Chen, Hui ^a   Wu, Emilia L ^b   Kaznessis, Yiannis N ^b   Ekdahl, Kristina N ^c,d   Nilsson, Bo ^d   Lambris, John D ^a  

^a UNIVERSITY OF PENNSYLVANIA   (United States)

^b University of Minnesota   (United States)

^c UPPSALA UNIVERSITY   (Sweden)

^d LINNAEUS UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

CLASSICAL COMPLEMENT PATHWAY C3 C5 CONVERTASE; COMPLEMENT COMPONENT C3; COMPLEMENT COMPONENT C3B; COMPLEMENT INHIBITOR; COMPSTATIN; MACROGLOBULIN; METHIONINE; THREONINE; UNCLASSIFIED DRUG; PROTEIN BINDING;

ADULT; AMINO ACID SUBSTITUTION; ARTICLE; BETA CHAIN; BINDING SITE; CASE REPORT; COMPLEMENT ACTIVATION; COMPLEMENT ALTERNATIVE PATHWAY; COMPLEMENT DEFICIENCY; COMPLEMENT INHIBITION; CONFORMATIONAL TRANSITION; ENZYME SUBSTRATE COMPLEX; EXON; FEMALE; GAIN OF FUNCTION MUTATION; HUMAN; LOSS OF FUNCTION MUTATION; MISSENSE MUTATION; MOLECULAR INTERACTION; MOLECULAR MODEL; MUTATIONAL ANALYSIS; OPSONIZATION; PATHOPHYSIOLOGY; POINT MUTATION; PRIORITY JOURNAL; PROTEIN DOMAIN; STRUCTURE ANALYSIS; SURFACE PROPERTY; CHEMICAL STRUCTURE; CHEMISTRY; DNA MUTATIONAL ANALYSIS; GENETICS; IMMUNOLOGY; METABOLISM; MUTATION; PEDIGREE; PROTEIN CONFORMATION;

ADULT; AMINO ACID SUBSTITUTION; COMPLEMENT ACTIVATION; COMPLEMENT C3; COMPLEMENT C3-C5 CONVERTASES; COMPLEMENT PATHWAY, ALTERNATIVE; DNA MUTATIONAL ANALYSIS; EXONS; FEMALE; HUMANS; MODELS, MOLECULAR; MUTATION; MUTATION, MISSENSE; PEDIGREE; PROTEIN BINDING; PROTEIN CONFORMATION; PROTEIN INTERACTION DOMAINS AND MOTIFS;

EID: 84925880932     PISSN: 00221767     EISSN: 15506606     Source Type: Journal    
DOI: 10.4049/jimmunol.1402781     Document Type: Article

References (52)

1. Ricklin, D., G. Hajishengallis, K. Yang, and J. D. Lambris. 2010. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11: 785-797.
2. Botto, M., M. Kirschfink, P. Macor, M. C. Pickering, R. Würzner, and F. Tedesco. 2009. Complement in human diseases: lessons from complement deficiencies. Mol. Immunol. 46: 2774-2783.
3. Degn, S. E., J. C. Jensenius, and S. Thiel. 2011. Disease-causing mutations in genes of the complement system. Am. J. Hum. Genet. 88: 689-705.
4. Lappegård, K. T., D. Christiansen, A. Pharo, E. B. Thorgersen, B. C. Hellerud, J. Lindstad, E. W. Nielsen, G. Bergseth, D. Fadnes, T. G. Abrahamsen, et al. 2009. Human genetic deficiencies reveal the roles of complement in the inflammatory network: lessons from nature. Proc. Natl. Acad. Sci. USA 106:15861-15866.
5. Ricklin, D., and J. D. Lambris. 2013. Complement in immune and inflammatory disorders: pathophysiological mechanisms. J. Immunol. 190: 3831-3838.
6. Skattum, L., M. van Deuren, T. van der Poll, and L. Truedsson. 2011. Complement deficiency states and associated infections. Mol. Immunol. 48: 1643-1655.
7. Rodríguez de Córdoba, S., C. L. Harris, B. P. Morgan, and O. Llorca. 2011. Lessons from functional and structural analyses of disease-associated genetic variants in the complement alternative pathway. Biochim. Biophys. Acta 1812: 12-22.
8. S Reis, E., D. A. Falcão, and L. Isaac. 2006. Clinical aspects and molecular basis of primary deficiencies of complement component C3 and its regulatory proteins factor I and factor H. Scand. J. Immunol. 63: 155-168.
9. Alper, C. A., H. R. Colten, F. S. Rosen, A. R. Rabson, G. M. Macnab, and J. S. Gear. 1972. Homozygous deficiency of C3 in a patient with repeated infections. Lancet 2: 1179-1181.
10. Figueroa, J. E., and P. Densen. 1991. Infectious diseases associated with complement deficiencies. Clin. Microbiol. Rev. 4: 359-395.
11. Pickering, M. C., M. Botto, P. R. Taylor, P. J. Lachmann, and M. J. Walport. 2000. Systemic lupus erythematosus, complement deficiency, and apoptosis. Adv. Immunol. 76: 227-324.
12. Frémeaux-Bacchi, V., E. C. Miller, M. K. Liszewski, L. Strain, J. Blouin, A. L. Brown, N. Moghal, B. S. Kaplan, R. A. Weiss, K. Lhotta, et al. 2008. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112: 4948-4952.
13. Martínez-Barricarte, R., M. Heurich, F. Valdes-Cañedo, E. Vazquez-Martul, E. Torreira, T. Montes, A. Tortajada, S. Pinto, M. Lopez-Trascasa, B. P. Morgan, et al. 2010. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J. Clin. Invest. 120: 3702-3712.
14. Thakkinstian, A., G. J. McKay, M. McEvoy, U. Chakravarthy, S. Chakrabarti, G. Silvestri, I. Kaur, X. Li, and J. Attia. 2011. Systematic review and meta-analysis of the association between complement component 3 and age-related macular degeneration: a HuGE review and meta-analysis. Am. J. Epidemiol. 173: 1365-1379.
15. Brown, K. M., E. Kondeatis, R. W. Vaughan, S. P. Kon, C. K. Farmer, J. D. Taylor, X. He, A. Johnston, C. Horsfield, B. J. Janssen, et al. 2006. Influence of donor C3 allotype on late renal-transplantation outcome. N. Engl. J. Med. 354: 2014-2023.
16. Goldberg, M., V. Fremeaux-Bacchi, P. Koch, Z. Fishelson, and Y. Katz. 2011. A novel mutation in the C3 gene and recurrent invasive pneumococcal infection: a clue for vaccine development. Mol. Immunol. 48: 1926-1931.
17. Sartz, L., A. I. Olin, A. C. Kristoffersson, A. L. Ståhl, M. E. Johansson, K. Westman, V. Fremeaux-Bacchi, K. Nilsson-Ekdahl, and D. Karpman. 2012. A novel C3 mutation causing increased formation of the C3 convertase in familial atypical hemolytic uremic syndrome. J. Immunol. 188: 2030-2037.
18. Nilsson, U. R., B. Nilsson, K. E. Storm, G. Sjölin-Forsberg, and R. Hällgren. 1992. Hereditary dysfunction of the third component of complement associated with a systemic lupus erythematosus-like syndrome and meningococcal meningitis. Arthritis Rheum. 35: 580-586.
19. Nilsson, B., U. R. Nilsson, A. Karlsson-Parra, G. Sjölin-Forsberg, and R. Hällgren. 1994. Reconstitution of the alternative pathway of complement by plasma infusions given to a patient with an SLE-like syndrome associated with a hereditary C3 dysfunction. Ann. Rheum. Dis. 53: 691-694.
20. de Bruijn, M. H., and G. H. Fey. 1985. Human complement component C3: cDNA coding sequence and derived primary structure. Proc. Natl. Acad. Sci. USA 82: 708-712.
21. Basta, M., and C. H. Hammer. 1991. A rapid FPLC method for purification of the third component of human and guinea pig complement. J. Immunol. Methods 142: 39-44.
22. Wu, J., Y. Q. Wu, D. Ricklin, B. J. Janssen, J. D. Lambris, and P. Gros. 2009. Structure of complement fragment C3b-factor H and implications for host protection by complement regulators. Nat. Immunol. 10: 728-733.
23. Sarrias, M. R., S. Franchini, G. Canziani, E. Argyropoulos, W. T. Moore, A. Sahu, and J. D. Lambris. 2001. Kinetic analysis of the interactions of complement receptor 2 (CR2, CD21) with its ligands C3d, iC3b, and the EBV glycoprotein gp350/220. J. Immunol. 167: 1490-1499.
24. Forneris, F., D. Ricklin, J. Wu, A. Tzekou, R. S. Wallace, J. D. Lambris, and P. Gros. 2010. Structures of C3b in complex with factors B and D give insight into complement convertase formation. Science 330: 1816-1820.
25. Katragadda, M., P. Magotti, G. Sfyroera, and J. D. Lambris. 2006. Hydrophobic effect and hydrogen bonds account for the improved activity of a complement inhibitor, compstatin. J. Med. Chem. 49: 4616-4622.
26. Mallik, B., M. Katragadda, L. A. Spruce, C. Carafides, C. G. Tsokos, D. Morikis, and J. D. Lambris. 2005. Design and NMR characterization of active analogues of compstatin containing non-natural amino acids. J. Med. Chem. 48: 274-286.
27. Isenman, D. E., D. I. Kells, N. R. Cooper, H. J. Müller-Eberhard, and M. K. Pangburn. 1981. Nucleophilic modification of human complement protein C3: correlation of conformational changes with acquisition of C3b-like functional properties. Biochemistry 20: 4458-4467.
28. Chen, H., D. Ricklin, M. Hammel, B. L. Garcia, W. J. McWhorter, G. Sfyroera, Y. Q. Wu, A. Tzekou, S. Li, B. V. Geisbrecht, et al. 2010. Allosteric inhibition of complement function by a staphylococcal immune evasion protein. Proc. Natl. Acad. Sci. USA 107: 17621-17626.
29. Schuster, M. C., D. Ricklin, K. Papp, K. S. Molnar, S. J. Coales, Y. Hamuro, G. Sfyroera, H. Chen, M. S. Winters, and J. D. Lambris. 2008. Dynamic structural changes during complement C3 activation analyzed by hydrogen/deuterium exchange mass spectrometry. Mol. Immunol. 45: 3142-3151.
30. Pantazatos, D., J. S. Kim, H. E. Klock, R. C. Stevens, I. A. Wilson, S. A. Lesley, and V. L. Woods, Jr. 2004. Rapid refinement of crystallographic protein construct definition employing enhanced hydrogen/deuterium exchange MS. Proc. Natl. Acad. Sci. USA 101: 751-756.
31. Zhang, Z., and D. L. Smith. 1993. Determination of amide hydrogen exchange by mass spectrometry: a new tool for protein structure elucidation. Protein Sci. 2: 522-531.
32. Janssen, B. J., E. F. Halff, J. D. Lambris, and P. Gros. 2007. Structure of compstatin in complex with complement component C3c reveals a new mechanism of complement inhibition. J. Biol. Chem. 282: 29241-29247.
33. Darden, T., D. York, and L. Pedersen. 1993. Particle mesh Ewald: An N·log(N) method for Ewald sums in large systems. J. Chem. Phys. 98: 10089-10092.
34. Ryckaert, J. P., G. Ciccotti, and H. J. C. Berendsen. 1977. Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J. Comput. Phys. 23: 327-341.
35. Cai, W., T. Sun, P. Liu, C. Chipot, and X. Shao. 2009. Inclusion mechanism of steroid drugs into beta-cyclodextrins. Insights from free energy calculations. J. Phys. Chem. B 113: 7836-7843.
36. Phillips, J. C., R. Braun, W. Wang, J. Gumbart, E. Tajkhorshid, E. Villa, C. Chipot, R. D. Skeel, L. Kalé, and K. Schulten. 2005. Scalable molecular dynamics with NAMD. J. Comput. Chem. 26: 1781-1802.
37. Janssen, B. J., E. G. Huizinga, H. C. Raaijmakers, A. Roos, M. R. Daha, K. Nilsson-Ekdahl, B. Nilsson, and P. Gros. 2005. Structures of complement component C3 provide insights into the function and evolution of immunity. Nature 437: 505-511.
38. 2O)Bb). Mol. Immunol. 45: 2370-2379.
39. Ricklin, D., A. Tzekou, B. L. Garcia, M. Hammel, W. J. McWhorter, G. Sfyroera, Y. Q. Wu, V. M. Holers, A. P. Herbert, P. N. Barlow, et al. 2009. A molecular insight into complement evasion by the staphylococcal complement inhibitor protein family. J. Immunol. 183: 2565-2574.
40. Rooijakkers, S. H., J. Wu, M. Ruyken, R. van Domselaar, K. L. Planken, A. Tzekou, D. Ricklin, J. D. Lambris, B. J. Janssen, J. A. van Strijp, and P. Gros. 2009. Structural and functional implications of the alternative complement pathway C3 convertase stabilized by a staphylococcal inhibitor. Nat. Immunol. 10: 721-727.
41. Ricklin, D. 2012. Manipulating the mediator: modulation of the alternative complement pathway C3 convertase in health, disease and therapy. Immunobiology 217: 1057-1066.
42. Ricklin, D., and J. D. Lambris. 2008. Compstatin: a complement inhibitor on its way to clinical application. Adv. Exp. Med. Biol. 632: 273-292.
43. Ricklin, D., and J. D. Lambris. 2013. Complement in immune and inflammatory disorders: therapeutic interventions. J. Immunol. 190: 3839-3847.
44. Laursen, N. S., K. R. Andersen, I. Braren, E. Spillner, L. Sottrup-Jensen, and G. R. Andersen. 2011. Substrate recognition by complement convertases revealed in the C5-cobra venom factor complex. EMBO J. 30: 606-616.
45. Schuster, M. C., H. Chen, and J. D. Lambris. 2007. Hydrogen/deuterium exchange mass spectrometry: potential for investigating innate immunity proteins. Adv. Exp. Med. Biol. 598: 407-417.
46. Harris, C. L., M. Heurich, S. Rodriguez de Cordoba, and B. P. Morgan. 2012. The complotype: dictating risk for inflammation and infection. Trends Immunol. 33: 513-521.
47. Rodriguez, E., P. M. Rallapalli, A. J. Osborne, and S. J. Perkins. 2014. New functional and structural insights from updated mutational databases for complement factor H, factor I, membrane cofactor protein and C3. Biosci. Rep. 34: 34.
48. Fan, X., Y. Yoshida, S. Honda, M. Matsumoto, Y. Sawada, M. Hattori, S. Hisanaga, R. Hiwa, F. Nakamura, M. Tomomori, et al. 2013. Analysis of genetic and predisposing factors in Japanese patients with atypical hemolytic uremic syndrome. Mol. Immunol. 54: 238-246.
49. Katschke, K. J., Jr., S. Stawicki, J. Yin, M. Steffek, H. Xi, L. Sturgeon, P. E. Hass, K. M. Loyet, L. Deforge, Y. Wu, et al. 2009. Structural and functional analysis of a C3b-specific antibody that selectively inhibits the alternative pathway of complement. J. Biol. Chem. 284: 10473-10479.
50. Wiesmann, C., K. J. Katschke, J. Yin, K. Y. Helmy, M. Steffek, W. J. Fairbrother, S. A. McCallum, L. Embuscado, L. DeForge, P. E. Hass, and M. van Lookeren Campagne. 2006. Structure of C3b in complex with CRIg gives insights into regulation of complement activation. Nature 444: 217-220.
51. Davies, K. A., J. A. Schifferli, and M. J. Walport. 1994. Complement deficiency and immune complex disease. Springer Semin. Immunopathol. 15: 397-416.
52. Reis, E. S., R. A. DeAngelis, H. Chen, R. R. Resuello, D. Ricklin, and J. D. Lambris. Therapeutic C3 inhibitor Cp40 abrogates complement activation induced by modern hemodialysis filters. Immunobiology DOI: 10.1016/j.imbio.2014.10.026.