Structural insights into the central complement component C3

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

doi:10.1016/j.molimm.2006.06.017

Cited by 65 publications

(47 citation statements)

References 67 publications

(51 reference statements)

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“…SCR2 and SCR3 of Ba were packed tightly into an antiparallel dimer capped by SCR1 (6). These structural data also indicate that SCR1 probably hinders access of the ligand C3b to the MIDAS of the vWA domain, and that the triad of SCR domains is probably only weakly associated with the vWA and SP domains.…”

mentioning

confidence: 69%

“…The ␣ЈNT and C345C domains in C3b include putative binding sites for fB required for C3 convertase formation (3)(4)(5). Both the ␣ЈNT and C345C domains are located in a part of the C3 molecule that undergoes large rearrangements upon activation of C3 into C3b, which explains why C3 does not interact with fB (6). Similarly, structural analyses have suggested that formation of the AP C3-convertase probably depends on the structure and orientation of the CUB domain of C3b and that the interaction between C3b and fB is independent of the TED domain (7).…”

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confidence: 99%

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3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase

Torreira

Tortajada

Montes

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Generation of the alternative pathway C3-convertase, the central amplification enzyme of the complement cascade, initiates by the binding of factor B (fB) to C3b to form the proconvertase, C3bB. C3bB is subsequently cleaved by factor D (fD) at a single site in fB, producing Ba and Bb fragments. Ba dissociates from the complex, while Bb remains bound to C3b, forming the active alternative pathway convertase, C3bBb. Using single-particle electron microscopy we have determined the 3-dimensional structures of the C3bB and the C3bBb complexes at Ϸ27Å resolution. The C3bB structure shows that fB undergoes a dramatic conformational change upon binding to C3b. However, the C3b-bound fB structure was easily interpreted after independently fitting the atomic structures of the isolated Bb and Ba fragments. Interestingly, the divalent cationbinding site in the von Willebrand type A domain in Bb faces the C345C domain of C3b, whereas the serine-protease domain of Bb points outwards. The structure also shows that the Ba fragment interacts with C3b separately from Bb at the level of the ␣ NT and CUB domains. Within this conformation, the long and flexible linker between Bb and Ba is likely exposed and accessible for cleavage by fD to form the active convertase, C3bBb. The architecture of the C3bB and C3bBb complexes reveals that C3b could promote cleavage and activation of fB by actively displacing the Ba domain from the von Willebrand type A domain in free fB. These structures provide a structural basis to understand fundamental aspects of the activation and regulation of the alternative pathway C3-convertase.C3 convertase ͉ electron microscopy ͉ factor B

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confidence: 69%

mentioning

confidence: 99%

3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase

Torreira

Tortajada

Montes

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…19 Activation of the classical, lectin, and alternative pathways results in cleavage of C3 to generate C3b and the anaphylatoxin C3a. When C3b is produced, the thioester is cleaved, and then this highly reactive species may bind covalently to targets.…”

Section: C3mentioning

confidence: 99%

Atypical Hemolytic Uremic Syndrome, Genetic Basis, and Clinical Manifestations

Kavanagh

Goodship

2011

Hematology

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Atypical hemolytic uremic syndrome (aHUS) is now well recognized to be a disease characterized by excessive complement activation in the microvasculature. In both the familial and sporadic forms, inherited and acquired abnormalities affecting components of the alternative complement pathway are found in ϳ 60% of patients. These include mutations in the genes encoding both complement regulators (factor H, factor I, membrane cofactor protein, and thrombomodulin) and activators (factors B and C3) and autoantibodies against factor H. Multiple hits are necessary for the disease to manifest, including a trigger, mutations, and at-risk haplotypes in complement genes. The prognosis for aHUS is poor, with most patients developing end-stage renal failure. Renal transplantation in most patients also has a poor prognosis, with frequent loss of the allograft to recurrent disease. However, improving results with combined liver-kidney transplantation and the advent of complement inhibitors such as eculizumab offer hope that the prognosis for aHUS will improve in future years.

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“…The CP, LP, and AP each induce assembly of C3 convertases that cleave complement component C3 to C3b, exposing a thioester domain that rapidly undergoes covalent linkage to hydroxyl or amine groups (7). In this way, C3b can become tethered to nearby surfaces.…”

mentioning

confidence: 99%

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

Kennedy

Schmidt

Thompson

et al. 2016

The Journal of Immunology

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The human complement system is the frontline defense mechanism against invading pathogens. The coexistence of humans and microbes throughout evolution has produced ingenious molecular mechanisms by which microorganisms escape complement attack. A common evasion strategy used by diverse pathogens is the hijacking of soluble human complement regulators to their surfaces to afford protection from complement activation. One such host regulator is factor H (FH), which acts as a negative regulator of complement to protect host tissues from aberrant complement activation. In this report, we show that Plasmodium falciparum merozoites, the invasive form of the malaria parasites, actively recruit FH and its alternative spliced form FH-like protein 1 when exposed to human serum. We have mapped the binding site in FH that recognizes merozoites and identified Pf92, a member of the six-cysteine family of Plasmodium surface proteins, as its direct interaction partner. When bound to merozoites, FH retains cofactor activity, a key function that allows it to downregulate the alternative pathway of complement. In P. falciparum parasites that lack Pf92, we observed changes in the pattern of C3b cleavage that are consistent with decreased regulation of complement activation. These results also show that recruitment of FH affords P. falciparum merozoites protection from complement-mediated lysis. Our study provides new insights on mechanisms of immune evasion of malaria parasites and highlights the important function of surface coat proteins in the interplay between complement regulation and successful infection of the host.

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Structural insights into the central complement component C3

Cited by 65 publications

References 67 publications

3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase

3D structure of the C3bB complex provides insights into the activation and regulation of the complement alternative pathway convertase

Atypical Hemolytic Uremic Syndrome, Genetic Basis, and Clinical Manifestations

Recruitment of Factor H as a Novel Complement Evasion Strategy for Blood-Stage Plasmodium falciparum Infection

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