Conformational Complexity of Complement Component C3

Janssen, B.J.C.; Gros, Piet

doi:10.1007/0-387-34134-x_20

Cited by 11 publications

(6 citation statements)

References 128 publications

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“…(B) Mutation of sidechains seen to coordinate SOS in SCR6 alter the affinity of FH67 402H for a heparin-HiTrap column. (C and D) Model for simultaneous FH binding to C3b (light blue spheres; PDB code, 2I07 [reference 26 ]) and GAGs (red/green spheres; PDB code, 1HPN [reference 27 ]) on the retinal epithelium. FH modules for which structural data is available are represented as cartoons and semitransparent surfaces: SCR5 ( 28 ), SCR6–8 (PDB code 2UWN; this study), SCR15/16 (Protein Data Bank ID, 1HFH [reference 29 ]), SCR19/20 (PDB code 2G7I/2BZM [references 30 , 31 ]).…”

Section: Resultsmentioning

confidence: 99%

Structural basis for complement factor H–linked age-related macular degeneration

Prosser

Johnson

Roversi

et al. 2007

The Journal of Experimental Medicine

167

213

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Nearly 50 million people worldwide suffer from age-related macular degeneration (AMD), which causes severe loss of central vision. A single-nucleotide polymorphism in the gene for the complement regulator factor H (FH), which causes a Tyr-to-His substitution at position 402, is linked to ∼50% of attributable risks for AMD. We present the crystal structure of the region of FH containing the polymorphic amino acid His402 in complex with an analogue of the glycosaminoglycans (GAGs) that localize the complement regulator on the cell surface. The structure demonstrates direct coordination of ligand by the disease-associated polymorphic residue, providing a molecular explanation of the genetic observation. This glycan-binding site occupies the center of an extended interaction groove on the regulator's surface, implying multivalent binding of sulfated GAGs. This finding is confirmed by structure-based site-directed mutagenesis, nuclear magnetic resonance–monitored binding experiments performed for both H402 and Y402 variants with this and another model GAG, and analysis of an extended GAG–FH complex.

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Section: Resultsmentioning

confidence: 99%

Structural basis for complement factor H–linked age-related macular degeneration

Prosser

Johnson

Roversi

et al. 2007

The Journal of Experimental Medicine

167

213

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“…Once activated, C3 convertases are formed (the alternative pathway forms C3bBb, and the classical pathway or the lectin pathway forms C4bC2a), which cleave C3 to C3a and C3b. C3b can indiscriminately bind to surfaces of microbes and host cells [17, 18]. On the surface of microbes or modified host cells, C3b and factor B form more C3 convertases, which produce more C3b.…”

Section: The Complement Systemmentioning

confidence: 99%

Familial Atypical Hemolytic Uremic Syndrome: A Review of Its Genetic and Clinical Aspects

Borsa

Ardissino

et al. 2012

Clinical and Developmental Immunology

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Atypical hemolytic uremic syndrome (aHUS) is a rare renal disease (two per one million in the USA) characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure. Both sporadic (80% of cases) and familial (20% of cases) forms are recognized. The study of familial aHUS has implicated genetic variation in multiple genes in the complement system in disease pathogenesis, helping to define the mechanism whereby complement dysregulation at the cell surface level leads to both sporadic and familial disease. This understanding has culminated in the use of Eculizumab as first-line therapy in disease treatment, significantly changing the care and prognosis of affected patients. However, even with this bright outlook, major challenges remain to understand the complexity of aHUS at the genetic level. It is possible that a more detailed picture of aHUS can be translated to an improved understanding of disease penetrance, which is highly variable, and response to therapy, both in the short and long terms.

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“…This results in activation of the terminal pathway of complement and finally to formation of membrane attack complex, lysis of the target cell, onset of inflammation, and macrophage or B-cell stimulation. 6,7 C3a is an anaphylatoxin, and C3b binds covalently to the surface of foreign and host cells. On host cell surface, the C3b fragment is inactivated by different soluble and membrane-bound inhibitors [ie, complement factors H and I, complement receptor 1 (CD35), membrane cofactor protein (CD46), and decay accelerating factor (CD55)].…”

mentioning

confidence: 99%

Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma

Riihilä

Nissinen

Farshchian

et al. 2017

The American Journal of Pathology

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Cutaneous squamous cell carcinoma (cSCC) is one of the most common metastatic skin cancers with increasing incidence. We examined the roles of complement component C3 and complement factor B (CFB) in the growth of cSCC. Analysis of cSCC cell lines (n = 8) and normal human epidermal keratinocytes (n = 11) with real-time quantitative PCR and Western blotting revealed up-regulation of C3 and CFB expression in cSCC cells. Immunohistochemical staining revealed stronger tumor cell-specific labeling for C3 and CFB in invasive cSCCs (n = 71) and recessive dystrophic epidermolysis bullosa-associated cSCCs (n = 11) than in cSCC in situ (n = 69), actinic keratoses (n = 63), and normal skin (n = 5). Significant up-regulation of C3 and CFB mRNA expression was noted in chemically induced mouse cSCCs, compared to benign papillomas. Knockdown of C3 and CFB expression inhibited migration and proliferation of cSCC cells and resulted in potent inhibition of extracellular signal-regulated kinase 1/2 activation. Knockdown of C3 and CFB markedly inhibited growth of human cSCC xenograft tumors in vivo. These results provide evidence for the roles of C3 and CFB in the development of cSCC and identify them as biomarkers and potential therapeutic targets in this metastatic skin cancer.

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Conformational Complexity of Complement Component C3

Cited by 11 publications

References 128 publications

Structural basis for complement factor H–linked age-related macular degeneration

Structural basis for complement factor H–linked age-related macular degeneration

Familial Atypical Hemolytic Uremic Syndrome: A Review of Its Genetic and Clinical Aspects

Complement Component C3 and Complement Factor B Promote Growth of Cutaneous Squamous Cell Carcinoma

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