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Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode.

Forneris F, Wu J, Xue X, Ricklin D, Lin Z, Sfyroera G, Tzekou A, Volokhina E, Granneman JC, Hauhart R, Bertram P, Liszewski MK, Atkinson JP, Lambris JD, Gros P
EMBO J 35 1133-49 (2016)
Related entries: 5fo7, 5fo8, 5foa, 5fob

Cited: 69 times
EuropePMC logo PMID: 27013439

Abstract

Regulators of complement activation (RCA) inhibit complement-induced immune responses on healthy host tissues. We present crystal structures of human RCA (MCP, DAF, and CR1) and a smallpox virus homolog (SPICE) bound to complement component C3b. Our structural data reveal that up to four consecutive homologous CCP domains (i-iv), responsible for inhibition, bind in the same orientation and extended arrangement at a shared binding platform on C3b. Large sequence variations in CCP domains explain the diverse C3b-binding patterns, with limited or no contribution of some individual domains, while all regulators show extensive contacts with C3b for the domains at the third site. A variation of ~100° rotation around the longitudinal axis is observed for domains binding at the fourth site on C3b, without affecting the overall binding mode. The data suggest a common evolutionary origin for both inhibitory mechanisms, called decay acceleration and cofactor activity, with variable C3b binding through domains at sites ii, iii, and iv, and provide a framework for understanding RCA disease-related mutations and immune evasion.

Reviews - 5fo9 mentioned but not cited (2)

  1. Complement component C3: A structural perspective and potential therapeutic implications. Geisbrecht BV, Lambris JD, Gros P. Semin Immunol 59 101627 (2022)
  2. Structural biology of complement receptors. Santos-López J, de la Paz K, Fernández FJ, Vega MC. Front Immunol 14 1239146 (2023)

Articles - 5fo9 mentioned but not cited (5)

  1. Regulators of complement activity mediate inhibitory mechanisms through a common C3b-binding mode. Forneris F, Wu J, Xue X, Ricklin D, Lin Z, Sfyroera G, Tzekou A, Volokhina E, Granneman JC, Hauhart R, Bertram P, Liszewski MK, Atkinson JP, Lambris JD, Gros P. EMBO J 35 1133-1149 (2016)
  2. Spatially conserved motifs in complement control protein domains determine functionality in regulators of complement activation-family proteins. Ojha H, Ghosh P, Singh Panwar H, Shende R, Gondane A, Mande SC, Sahu A. Commun Biol 2 290 (2019)
  3. Complement Activation in the Central Nervous System: A Biophysical Model for Immune Dysregulation in the Disease State. Peoples N, Strang C. Front Mol Neurosci 14 620090 (2021)
  4. Interaction Analysis of Adenovirus L5 Protein With Pancreatic Cancer Cell Surface Receptor to Analyze Its Affinity for Oncolytic Virus Therapy. Nisar M, Paracha RZ, Gul A, Arshad I, Ejaz S, Murad D, Khan S, Mustansar Z. Front Oncol 12 832277 (2022)
  5. Molecular Simulation Study on the Interaction between Porcine CR1-like and C3b. Hou Z, Yin W, Hao Z, Fan K, Sun N, Sun P, Li H. Molecules 28 2183 (2023)


Reviews citing this publication (21)

  1. Novel mechanisms and functions of complement. Hajishengallis G, Reis ES, Mastellos DC, Ricklin D, Lambris JD. Nat Immunol 18 1288-1298 (2017)
  2. Complement component C3 - The "Swiss Army Knife" of innate immunity and host defense. Ricklin D, Reis ES, Mastellos DC, Gros P, Lambris JD. Immunol Rev 274 33-58 (2016)
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  8. Complement Dysregulation and Disease: Insights from Contemporary Genetics. Liszewski MK, Java A, Schramm EC, Atkinson JP. Annu Rev Pathol 12 25-52 (2017)
  9. Structural insight into proteolytic activation and regulation of the complement system. Schatz-Jakobsen JA, Pedersen DV, Andersen GR. Immunol Rev 274 59-73 (2016)
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  16. Liposomes to Augment Dialysis in Preclinical Models: A Structured Review. Hart K, Harvey M, Tang M, Wu Z, Cave G. Pharmaceutics 13 395 (2021)
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  18. A guide to complement biology, pathology and therapeutic opportunity. Mastellos DC, Hajishengallis G, Lambris JD. Nat Rev Immunol (2023)
  19. Post-Transplant Thrombotic Microangiopathy due to a Pathogenic Mutation in Complement Factor I in a Patient With Membranous Nephropathy: Case Report and Review of Literature. Saleem M, Shaikh S, Hu Z, Pozzi N, Java A. Front Immunol 13 909503 (2022)
  20. Role of Complement in the Onset of Age-Related Macular Degeneration. Piri N, Kaplan HJ. Biomolecules 13 832 (2023)
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Articles citing this publication (41)

  1. Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses. Xue X, Wu J, Ricklin D, Forneris F, Di Crescenzio P, Schmidt CQ, Granneman J, Sharp TH, Lambris JD, Gros P. Nat Struct Mol Biol 24 643-651 (2017)
  2. Insights into IgM-mediated complement activation based on in situ structures of IgM-C1-C4b. Sharp TH, Boyle AL, Diebolder CA, Kros A, Koster AJ, Gros P. Proc Natl Acad Sci U S A 116 11900-11905 (2019)
  3. Antibody-drug conjugate targeting CD46 eliminates multiple myeloma cells. Sherbenou DW, Aftab BT, Su Y, Behrens CR, Wiita A, Logan AC, Acosta-Alvear D, Hann BC, Walter P, Shuman MA, Wu X, Atkinson JP, Wolf JL, Martin TG, Liu B. J Clin Invest 126 4640-4653 (2016)
  4. Therapeutic Targeting of the Complement System: From Rare Diseases to Pandemics. Garred P, Tenner AJ, Mollnes TE. Pharmacol Rev 73 792-827 (2021)
  5. Functional and structural insight into properdin control of complement alternative pathway amplification. Pedersen DV, Roumenina L, Jensen RK, Gadeberg TA, Marinozzi C, Picard C, Rybkine T, Thiel S, Sørensen UB, Stover C, Fremeaux-Bacchi V, Andersen GR. EMBO J 36 1084-1099 (2017)
  6. Functional Characterization of Alternative and Classical Pathway C3/C5 Convertase Activity and Inhibition Using Purified Models. Zwarthoff SA, Berends ETM, Mol S, Ruyken M, Aerts PC, Józsi M, de Haas CJC, Rooijakkers SHM, Gorham RD. Front Immunol 9 1691 (2018)
  7. Structural Basis for Properdin Oligomerization and Convertase Stimulation in the Human Complement System. Pedersen DV, Gadeberg TAF, Thomas C, Wang Y, Joram N, Jensen RK, Mazarakis SMM, Revel M, El Sissy C, Petersen SV, Lindorff-Larsen K, Thiel S, Laursen NS, Fremeaux-Bacchi V, Andersen GR. Front Immunol 10 2007 (2019)
  8. Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. Su Y, Liu Y, Behrens CR, Bidlingmaier S, Lee NK, Aggarwal R, Sherbenou DW, Burlingame AL, Hann BC, Simko JP, Premasekharan G, Paris PL, Shuman MA, Seo Y, Small EJ, Liu B. JCI Insight 3 121497 (2018)
  9. Decreased complement C3 levels are associated with poor prognosis in patients with COVID-19: A retrospective cohort study. Fang S, Wang H, Lu L, Jia Y, Xia Z. Int Immunopharmacol 89 107070 (2020)
  10. Insights Into Enhanced Complement Activation by Structures of Properdin and Its Complex With the C-Terminal Domain of C3b. van den Bos RM, Pearce NM, Granneman J, Brondijk THC, Gros P. Front Immunol 10 2097 (2019)
  11. A potent complement factor C3-specific nanobody inhibiting multiple functions in the alternative pathway of human and murine complement. Jensen RK, Pihl R, Gadeberg TAF, Jensen JK, Andersen KR, Thiel S, Laursen NS, Andersen GR. J Biol Chem 293 6269-6281 (2018)
  12. Structural Implications for the Formation and Function of the Complement Effector Protein iC3b. Papanastasiou M, Koutsogiannaki S, Sarigiannis Y, Geisbrecht BV, Ricklin D, Lambris JD. J Immunol 198 3326-3335 (2017)
  13. Genotype-phenotype correlations of low-frequency variants in the complement system in renal disease and age-related macular degeneration. Geerlings MJ, Volokhina EB, de Jong EK, van de Kar N, Pauper M, Hoyng CB, van den Heuvel LP, den Hollander AI. Clin Genet 94 330-338 (2018)
  14. Complement therapeutics meets nanomedicine: overcoming human complement activation and leukocyte uptake of nanomedicines with soluble domains of CD55. Gifford G, Vu VP, Banda NK, Holers VM, Wang G, Groman EV, Backos D, Scheinman R, Moghimi SM, Simberg D. J Control Release 302 181-189 (2019)
  15. Elucidating the Immune Evasion Mechanisms of Borrelia mayonii, the Causative Agent of Lyme Disease. Walter L, Sürth V, Röttgerding F, Zipfel PF, Fritz-Wolf K, Kraiczy P. Front Immunol 10 2722 (2019)
  16. The J-elongated conformation of β2-glycoprotein I predominates in solution: implications for our understanding of antiphospholipid syndrome. Ruben E, Planer W, Chinnaraj M, Chen Z, Zuo X, Pengo V, De Filippis V, Alluri RK, McCrae KR, Macor P, Tedesco F, Pozzi N. J Biol Chem 295 10794-10806 (2020)
  17. The Sez6 Family Inhibits Complement by Facilitating Factor I Cleavage of C3b and Accelerating the Decay of C3 Convertases. Qiu WQ, Luo S, Ma SA, Saminathan P, Li H, Gunnersen JM, Gelbard HA, Hammond JW. Front Immunol 12 607641 (2021)
  18. A C3-specific nanobody that blocks all three activation pathways in the human and murine complement system. Pedersen H, Jensen RK, Hansen AG, Gadeberg TAF, Thiel S, Laursen NS, Andersen GR. J Biol Chem 295 8746-8758 (2020)
  19. C1q and Mannose-Binding Lectin Interact with CR1 in the Same Region on CCP24-25 Modules. Jacquet M, Cioci G, Fouet G, Bally I, Thielens NM, Gaboriaud C, Rossi V. Front Immunol 9 453 (2018)
  20. Seizure protein 6 controls glycosylation and trafficking of kainate receptor subunits GluK2 and GluK3. Pigoni M, Hsia HE, Hartmann J, Rudan Njavro J, Shmueli MD, Müller SA, Güner G, Tüshaus J, Kuhn PH, Kumar R, Gao P, Tran ML, Ramazanov B, Blank B, Hipgrave Ederveen AL, Von Blume J, Mulle C, Gunnersen JM, Wuhrer M, Rammes G, Busche MA, Koeglsperger T, Lichtenthaler SF. EMBO J 39 e103457 (2020)
  21. A Multimodality Approach to Assessing Factor I Genetic Variants in Atypical Hemolytic Uremic Syndrome. Java A, Pozzi N, Love-Gregory LD, Heusel JW, Sung YJ, Hu Z, Bertram P, Liszewski MK, Cline LM, Ren Z, Atkinson JP. Kidney Int Rep 4 1007-1017 (2019)
  22. An allosteric redox switch in domain V of β2-glycoprotein I controls membrane binding and anti-domain I autoantibody recognition. Kumar S, Chinnaraj M, Planer W, Zuo X, Macor P, Tedesco F, Pozzi N. J Biol Chem 297 100890 (2021)
  23. Invariant surface glycoprotein 65 of Trypanosoma brucei is a complement C3 receptor. Macleod OJS, Cook AD, Webb H, Crow M, Burns R, Redpath M, Seisenberger S, Trevor CE, Peacock L, Schwede A, Kimblin N, Francisco AF, Pepperl J, Rust S, Voorheis P, Gibson W, Taylor MC, Higgins MK, Carrington M. Nat Commun 13 5085 (2022)
  24. Complement Inhibitors Block Complement C3 Opsonization and Improve Targeting Selectivity of Nanoparticles in Blood. Gaikwad H, Li Y, Gifford G, Groman E, Banda NK, Saba L, Scheinman R, Wang G, Simberg D. Bioconjug Chem 31 1844-1856 (2020)
  25. Cutaneous Vasculitis and Digital Ischaemia Caused by Heterozygous Gain-of-Function Mutation in C3. Omoyinmi E, Mohamoud I, Gilmour K, Brogan PA, Eleftheriou D. Front Immunol 9 2524 (2018)
  26. Insight into mode-of-action and structural determinants of the compstatin family of clinical complement inhibitors. Lamers C, Xue X, Smieško M, van Son H, Wagner B, Berger N, Sfyroera G, Gros P, Lambris JD, Ricklin D. Nat Commun 13 5519 (2022)
  27. Ionic tethering contributes to the conformational stability and function of complement C3b. López-Perrote A, Harrison RE, Subías M, Alcorlo M, Rodríguez de Córdoba S, Morikis D, Llorca O. Mol Immunol 85 137-147 (2017)
  28. Molecular engineering of an efficient four-domain DAF-MCP chimera reveals the presence of functional modularity in RCA proteins. Panwar HS, Ojha H, Ghosh P, Barage SH, Raut S, Sahu A. Proc Natl Acad Sci U S A 116 9953-9958 (2019)
  29. Species Specificity of Vaccinia Virus Complement Control Protein for the Bovine Classical Pathway Is Governed Primarily by Direct Interaction of Its Acidic Residues with Factor I. Kumar J, Yadav VN, Phulera S, Kamble A, Gautam AK, Panwar HS, Sahu A. J Virol 91 e00668-17 (2017)
  30. Edwardsiella tarda TraT is an anti-complement factor and a cellular infection promoter. Li M, Wu M, Sun Y, Sun L. Commun Biol 5 637 (2022)
  31. Multifaceted Activities of Seven Nanobodies against Complement C4b. De la O Becerra KI, Oosterheert W, van den Bos RM, Xenaki KT, Lorent JH, Ruyken M, Schouten A, Rooijakkers SHM, van Bergen En Henegouwen PMP, Gros P. J Immunol 208 2207-2219 (2022)
  32. The β-Secretase Substrate Seizure 6-Like Protein (SEZ6L) Controls Motor Functions in Mice. Ong-Pålsson E, Njavro JR, Wilson Y, Pigoni M, Schmidt A, Müller SA, Meyer M, Hartmann J, Busche MA, Gunnersen JM, Munro KM, Lichtenthaler SF. Mol Neurobiol 59 1183-1198 (2022)
  33. Functional Hemolytic Test for Complement Alternative Pathway Convertase Activity. Michels MAHM, van de Kar NCAJ, Volokhina EB, van den Heuvel BLPWJ. Methods Mol Biol 2227 83-96 (2021)
  34. Insights Into the Structure-Function Relationships of Dimeric C3d Fragments. Wahid AA, Dunphy RW, Macpherson A, Gibson BG, Kulik L, Whale K, Back C, Hallam TM, Alkhawaja B, Martin RL, Meschede I, Laabei M, Lawson ADG, Holers VM, Watts AG, Crennell SJ, Harris CL, Marchbank KJ, van den Elsen JMH. Front Immunol 12 714055 (2021)
  35. Novel homozygous CD46 variant with C-isoform expression affects C3b inactivation in atypical hemolytic uremic syndrome. Schack VR, Herlin MK, Pedersen H, Jensen JMB, Faerch M, Bundgaard B, Jensen RK, Jensen UB, Christensen R, Andersen GR, Thiel S, Höllsberg P. Eur J Immunol 52 1610-1619 (2022)
  36. Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition. Narkhede YB, Gautam AK, Hsu RV, Rodriguez W, Zewde NT, Harrison RES, Arantes PR, Gaieb Z, Gorham RD, Kieslich C, Morikis D, Sahu A, Palermo G. Front Mol Biosci 8 618068 (2021)
  37. A Monoclonal Antibody That Provides a Model for C3 Nephritic Factors. Hourcade DE, Mitchell LM. Monoclon Antib Immunodiagn Immunother 42 9-14 (2023)
  38. Identification of SARS-CoV-2 Main Protease (Mpro) Cleavage Sites Using Two-Dimensional Electrophoresis and In Silico Cleavage Site Prediction. Miltner N, Kalló G, Csősz É, Miczi M, Nagy T, Mahdi M, Mótyán JA, Tőzsér J. Int J Mol Sci 24 3236 (2023)
  39. Mutations in atypical hemolytic uremic syndrome provide evidence for the role of calcium in complement factor I. Java A, Atkinson J, Hu Z, Pozzi N. Blood 142 607-610 (2023)
  40. New Insights into the Complement Receptor of the Ig Superfamily Obtained from Structural and Functional Studies on Two Mutants. Duan H, Abram TG, Cruz AR, Rooijakkers SHM, Geisbrecht BV. Immunohorizons 7 806-818 (2023)
  41. Structural Model for Factor X Inhibition of IgM and Complement-Mediated Neutralization of Adenovirus. Wagner N, Shayakhmetov DM, Stewart PL. Viruses 15 1343 (2023)


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