[1] Complement factor I and cofactors in control of complement system convertase enzymes

Sim, Robert B.; Aj, Day; Be, Moffatt; Fontaine, Marc

doi:10.1016/0076-6879(93)23035-l

Cited by 98 publications

(91 citation statements)

References 52 publications

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“…Human fI was purified from citrated, outdated human serum from the blood bank (HD Supplies) with three minor modifications of the protocol described in ref. 44: (i) the serum was clarified by centrifugation; (ii) no protease inhibitors were used; and (iii) size-exclusion chromatography fractions containing fI in Tris-buffered saline (pH 7.2) were pooled and cleaned of IgGs and albumin with a Hi-Trap protein-G column (GE Healthcare) and an anti-human serum albumin column, respectively.…”

Section: Methodsmentioning

confidence: 99%

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

Roversi

Johnson

Caesar

et al. 2011

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

124

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The complement system is a key component of innate and adaptive immune responses. Complement regulation is critical for prevention and control of disease. We have determined the crystal structure of the complement regulatory enzyme human factor I (fI). FI is in a proteolytically inactive form, demonstrating that it circulates in a zymogen-like state despite being fully processed to the mature sequence. Mapping of functional data from mutants of fI onto the structure suggests that this inactive form is maintained by the noncatalytic heavy-chain allosterically modulating activity of the light chain. Once the ternary complex of fI, a cofactor and a substrate is formed, the allosteric inhibition is released, and fI is oriented for cleavage. In addition to explaining how circulating fI is limited to cleaving only C3b/C4b, our model explains the molecular basis of disease-associated polymorphisms in fI and its cofactors. T he complement system is a major component of innate and adaptive immunity whose efficient regulation is critical for prevention and control of disease (1). This regulation is effected by host cells expressing and recruiting a series of proteins that protect them from complement-mediated destruction. A key step in this self-protection is the proteolytic cleavage of complement C3b (and its homolog C4b) by the serine protease complement factor I (fI) (2) in the presence of additional regulatory proteins termed "cofactors" (3). In the absence of regulation by fI the alternative pathway of complement leads to continuous generation of fluid-phase and cell-surface-deposited C3b by a self-amplification loop: The more C3 is converted to C3b, the more C3 convertases are formed, resulting in the depletion of C3 (4). With healthy levels of functional fI and its cofactors, the irreversible breakdown of C3b to iC3b has three effects: (i) arrest of the assembly of the C3 convertases on hostcell surfaces, thus avoiding inappropriate complement amplification; (ii) prevention of runaway C3 consumption in the fluid phase; and (iii) generation of the C3b cleavage fragments that go on to bind specific complement receptors and are involved in opsonization and triggering of the adaptive immune response (5). The importance of this regulatory mechanism is highlighted by the fact that fI-deficient individuals suffer from recurring infections and that polymorphisms in or near the genes for fI (and its cofactors) can predispose the carriers to diseases such as systemic lupus erythematosus, atypical hemolytic-uremic syndrome (aHUS), membranoproliferative glomerulonephritis, and age-related macular degeneration (for a recent review, see ref. 6).During the last few years, biochemical and structural data for complement regulators and C3/C3b in complex with regulators and inhibitors (7-11) have significantly advanced our understanding of the molecular mechanisms underlying complement regulation (12). To date, however, only low-resolution information about fI has been available (13, 14). FI is synthesized as a single 66-kDa chain an...

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Section: Methodsmentioning

confidence: 99%

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

Roversi

Johnson

Caesar

et al. 2011

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

124

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“…The domain structure of the astacin family represents a pattern seen in several protease families, such as the coagulation proteases, complement proteases, proprotein convertases, and matrixins (Furie & Furie, 1988;Matrisian, 1992;Steiner et al, 1992;Sim et al, 1993). The various members of these families result from gene duplication, evolution, gene fusion, and exon shuffling.…”

Section: Comm)mentioning

confidence: 99%

“…The noncovalent interactions of astacin family members with membranes and complexes may serve to restrict movement of the active proteases and concentrate activity at specific sites. Investigations of the factors that determine these interactions may have relevance to other proteolytic systems that function at the cell surface, such as complement proteases, plasminogen activators, and matrix metalloproteases (Vassalli et al, 1991;Sim et al, 1993;Strongin et al, 1995).…”

Section: Oligomeric Structure and Membrane Associationmentioning

confidence: 99%

“…For complement proteases, there is evidence that Clr/s mediates calciumdependent tetrameric complex formation between two Clr-Cls dimers and the association of this complex with Clq to form the mature C1 molecule (e.g., Sim et al, 1993). Childs and O'Connor (1994), studying Drosophila tolloid, found that loss-offunction mutations map to CUB repeats.…”

Section: Interaction Domains/cub Domainsmentioning

confidence: 99%

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The astacin family of metalloendopeptidases

1995

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The astacin family of metalloendopeptidases was recognized as a novel family of proteases in the 1990s. The crayfish enzyme astacin was the first characterized and is one of the smallest members of the family. More than 20 members of the family have now been identified. They have been detected in species ranging from hydra to humans, in mature and in developmental systems. Proposed functions of these proteases include activation of growth factors, degradation of polypeptides, and processing of extracellular proteins. Astacin family proteases are synthesized with NH,-terminal signal and proenzyme sequences, and many (such as meprins, BMP-1, folloid) contain multiple domains COOH-terminal to the protease domain. They are either secreted from cells or are plasma membrane-associated enzymes. They have some distinguishing features in addition to the signature sequence in the protease domain: HEXXHXXGFXHEXXRXDR. They have a unique type of zinc binding, with pentacoordination, and a protease domain tertiary structure that contains common attributes with serralysins, matrix metalloendopeptidases, and snake venom proteases; they cleave peptide bonds in polypeptides such as insulin B chain and bradykinin and in proteins such as casein and gelatin; and they have arylamidase activity. Meprins are unique proteases in the astacin family, and indeed in the animal kingdom, in their oligomeric structure; they are dimers of disulfide-linked dimers and are highly glycosylated, type I integral membrane proteins that have many attributes of receptors or integrins with adhesion, epidermal growth factor-like, and transmembrane domains. The 01 and /3 subunits are differentially expressed and processed to yield latent and active proteases as well as membraneassociated and secreted forms. Meprins represent excellent models of hetero-and homo-oligomeric enzymes that are regulated at the transcriptional and posttranslational levels.

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“…FI is an 88 kDa glycoprotein that circulates in blood and inhibits all pathways of complement. It degrades activated complement factors C4b and C3b, but only when they are bound to a cofactor such as FH, C4BP, CR1 or MCP (Sim et al, 1993). Structurally, FI is a heterodimer of a heavy chain consisting of one FI--membrane attack complex (FIMAC) domain, one CD5 domain and two low--density lipoprotein receptor domains (LDLR), and a light chain containing the serine protease, linked together by a disulfide bond.…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency

Nita

Genel

Nilsson

et al. 2011

Molecular Immunology

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[1] Complement factor I and cofactors in control of complement system convertase enzymes

Cited by 98 publications

References 52 publications

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

Structural basis for complement factor I control and its disease-associated sequence polymorphisms

The astacin family of metalloendopeptidases

Molecular characterization of two novel cases of complete complement inhibitor Factor I deficiency

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