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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)
Cited: 66 times
EuropePMC logo PMID: 28671664

Abstract

The complement system labels microbes and host debris for clearance. Degradation of surface-bound C3b is pivotal to direct immune responses and protect host cells. How the serine protease factor I (FI), assisted by regulators, cleaves either two or three distant peptide bonds in the CUB domain of C3b remains unclear. We present a crystal structure of C3b in complex with FI and regulator factor H (FH; domains 1-4 with 19-20). FI binds C3b-FH between FH domains 2 and 3 and a reoriented C3b C-terminal domain and docks onto the first scissile bond, while stabilizing its catalytic domain for proteolytic activity. One cleavage in C3b does not affect its overall structure, whereas two cleavages unfold CUB and dislodge the thioester-containing domain (TED), affecting binding of regulators and thereby determining the number of cleavages. These data explain how FI generates late-stage opsonins iC3b or C3dg in a context-dependent manner, to react to foreign, danger or healthy self signals.

Reviews - 5o35 mentioned but not cited (1)

  1. Complement component C3: A structural perspective and potential therapeutic implications. Geisbrecht BV, Lambris JD, Gros P. Semin Immunol 59 101627 (2022)

Articles - 5o35 mentioned but not cited (6)

  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. Structure-Guided Engineering of a Complement Component C3-Binding Nanobody Improves Specificity and Adds Cofactor Activity. Pedersen H, Jensen RK, Hansen AG, Petersen SV, Thiel S, Laursen NS, Andersen GR. Front Immunol 13 872536 (2022)
  3. A receptor for the complement regulator factor H increases transmission of trypanosomes to tsetse flies. Macleod OJS, Bart JM, MacGregor P, Peacock L, Savill NJ, Hester S, Ravel S, Sunter JD, Trevor C, Rust S, Vaughan TJ, Minter R, Mohammed S, Gibson W, Taylor MC, Higgins MK, Carrington M. Nat Commun 11 1326 (2020)
  4. Identification and Characterization of chCR2, a Protein That Binds Chicken Complement Component 3d. Jin H, Kong Z, Jiang B, Tu M, Xu J, Cheng J, Liu W, Zhang Z, Li Y. J Immunol 210 1408-1418 (2023)
  5. 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)
  6. 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)


Reviews citing this publication (14)

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  3. Be on Target: Strategies of Targeting Alternative and Lectin Pathway Components in Complement-Mediated Diseases. Dobó J, Kocsis A, Gál P. Front Immunol 9 1851 (2018)
  4. The role of the alternative pathway of complement activation in glomerular diseases. Łukawska E, Polcyn-Adamczak M, Niemir ZI. Clin. Exp. Med. 18 297-318 (2018)
  5. Tuning the Functionality by Splicing: Factor H and Its Alternative Splice Variant FHL-1 Share a Gene but Not All Functions. Mannes M, Dopler A, Huber-Lang M, Schmidt CQ. Front Immunol 11 596415 (2020)
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  7. Proprotein Convertases and the Complement System. Dobó J, Kocsis A, Dani R, Gál P. Front Immunol 13 958121 (2022)
  8. Protein therapeutics and their lessons: Expect the unexpected when inhibiting the multi-protein cascade of the complement system. Schmidt CQ, Smith RJH. Immunol Rev 313 376-401 (2023)
  9. Self-Damage Caused by Dysregulation of the Complement Alternative Pathway: Relevance of the Factor H Protein Family. Sánchez-Corral P, Pouw RB, López-Trascasa M, Józsi M. Front Immunol 9 1607 (2018)
  10. Structural studies offer a framework for understanding the role of properdin in the alternative pathway and beyond. Pedersen DV, Lorentzen J, Andersen GR. Immunol Rev 313 46-59 (2023)
  11. The Challenges and Promise of Complement Therapeutics for Ocular Diseases. Park DH, Connor KM, Lambris JD. Front Immunol 10 1007 (2019)
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  2. 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)
  3. Predicted structural mimicry of spike receptor-binding motifs from highly pathogenic human coronaviruses. Beaudoin CA, Jamasb AR, Alsulami AF, Copoiu L, van Tonder AJ, Hala S, Bannerman BP, Thomas SE, Vedithi SC, Torres PHM, Blundell TL. Comput Struct Biotechnol J 19 3938-3953 (2021)
  4. Biophysical analysis of sialic acid recognition by the complement regulator Factor H. Schmidt CQ, Hipgrave Ederveen AL, Harder MJ, Wuhrer M, Stehle T, Blaum BS. Glycobiology 28 765-773 (2018)
  5. Self versus Nonself Discrimination by the Soluble Complement Regulators Factor H and FHL-1. Dopler A, Guntau L, Harder MJ, Palmer A, Höchsmann B, Schrezenmeier H, Simmet T, Huber-Lang M, Schmidt CQ. J Immunol 202 2082-2094 (2019)
  6. 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)
  7. 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)
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  9. Analysis of C3 Gene Variants in Patients With Idiopathic Recurrent Spontaneous Pregnancy Loss. Mohlin FC, Gros P, Mercier E, Gris JR, Blom AM. Front Immunol 9 1813 (2018)
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  11. Genes and SNPs Involved with Scrotal and Umbilical Hernia in Pigs. Rodrigues AFG, Ibelli AMG, Peixoto JO, Cantão ME, Oliveira HC, Savoldi IR, Souza MR, Mores MAZ, Carreño LOD, Ledur MC. Genes (Basel) 12 166 (2021)
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  14. 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)
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  17. 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)
  18. A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negative CFI variants in age-related macular degeneration. Hallam TM, Cox TE, Smith-Jackson K, Brocklebank V, Baral AJ, Tzoumas N, Steel DH, Wong EKS, Shuttleworth VG, Lotery AJ, Harris CL, Marchbank KJ, Kavanagh D. Front Immunol 13 1028760 (2022)
  19. An Evaluation of the Complement-Regulating Activities of Human Complement Factor H (FH) Variants Associated With Age-Related Macular Degeneration. Biggs RM, Makou E, Lauder S, Herbert AP, Barlow PN, Katti SK. Invest Ophthalmol Vis Sci 63 30 (2022)
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  22. Complement component 3 mutations alter the longitudinal risk of pediatric malaria and severe malarial anemia. Raballah E, Anyona SB, Cheng Q, Munde EO, Hurwitz IF, Onyango C, Ndege C, Hengartner NW, Pacheco MA, Escalante AA, Lambert CG, Ouma C, Obama HCJT, Schneider KA, Seidenberg PD, McMahon BH, Perkins DJ. Exp Biol Med (Maywood) 247 672-682 (2022)
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  24. Deconstruction of Neurotrypsin Reveals a Multi-factorially Regulated Activity Affecting Myotube Formation and Neuronal Excitability. Canciani A, Capitanio C, Stanga S, Faravelli S, Scietti L, Mapelli L, Soda T, D'Angelo E, Kienlen-Campard P, Forneris F. Mol Neurobiol 59 7466-7485 (2022)
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  28. Functional Characterization of Rare Genetic Variants in the N-Terminus of Complement Factor H in aHUS, C3G, and AMD. Wong EKS, Hallam TM, Brocklebank V, Walsh PR, Smith-Jackson K, Shuttleworth VG, Cox TE, Anderson HE, Barlow PN, Marchbank KJ, Harris CL, Kavanagh D. Front Immunol 11 602284 (2020)
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  30. Functional and Expressional Analyses Reveal the Distinct Role of Complement Factor I in Regulating Complement System Activation during GCRV Infection in Ctenopharyngodon idella. Liu Y, Lv Z, Xiao T, Zhang X, Ding C, Qin B, Xu B, Liu Q. Int J Mol Sci 23 11369 (2022)
  31. Functional characterization of 105 factor H variants associated with aHUS: lessons for variant classification. Martín Merinero H, Zhang Y, Arjona E, Del Angel G, Goodfellow R, Gomez-Rubio E, Ji RR, Michelena M, Smith RJH, Rodríguez de Córdoba S. Blood 138 2185-2201 (2021)
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  33. Group B Streptococcus Surface Protein β: Structural Characterization of a Complement Factor H-Binding Motif and Its Contribution to Immune Evasion. Xu X, Lewis Marffy AL, Keightley A, McCarthy AJ, Geisbrecht BV. J Immunol 208 1232-1247 (2022)
  34. Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation. Gerogianni A, Dimitrov JD, Zarantonello A, Poillerat V, Chonat S, Sandholm K, McAdam KE, Ekdahl KN, Mollnes TE, Mohlin C, Roumenina LT, Nilsson PH. Front Immunol 13 901876 (2022)
  35. 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)
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  37. 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)
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