A novel murine complement-related gene encoding a C1r-like serum protein

Circolo, Antonella; Garnier, Gérard; Volanakis, John E.

doi:10.1016/s0161-5890(02)00283-3

Cited by 11 publications

(9 citation statements)

References 39 publications

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“…Restriction fragment subcloning allowed sequencing of the entire c1rA and c1sA genes, except for 2 and 3 intronic gaps respectively. It also led to the identification of a C1r-related gene (c1r-LP) located 5h to c1rA as described previously [29]. The C1r-LP gene is expressed mainly in the liver and encodes a serum protein of unknown function, structurally related to C1rA but missing the region from the EGF module to the beginning of the second CCP of C1rA.…”

Section: Characterization Of the C1sa C1ra And C1rb Genesmentioning

confidence: 80%

Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system

Garnier

Circolo

et al. 2003

Biochemical Journal

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C1r and C1s are the serine proteases that form the catalytic unit of the C1 complex, the first component of complement. In the present study, we found that the genes encoding murine C1r and C1s are duplicated. One set of these genes, referred to as c1rA and c1sA, are primarily expressed in the liver and are therefore the homologues of the human C1r and C1s genes. The other two genes, termed c1rB and c1sB, are expressed exclusively in male reproductive tissues, specifically the coagulating gland and the prostate. The predicted C1rB and C1sB proteins share 96 and 93% amino acid identity with C1rA and C1sA respectively. Most of the substitutions are clustered in the serine protease domains, suggesting differences in catalytic efficiencies and/or substrate specificities or alternatively adaptation to different physiological environments. The high homology of C1rB and C1sB with C1rA and C1sA in the non-catalytic regions indicates that they are probably capable of assembling the C1 complex. The expression of alternative genes encoding isomorphs of activating components of complement in male reproductive tissues raises the possibility of new mechanisms of complement activation in the male genital tract or of novel functions for complement proteases in reproduction.

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Section: Characterization Of the C1sa C1ra And C1rb Genesmentioning

confidence: 80%

Complement C1r and C1s genes are duplicated in the mouse: differential expression generates alternative isomorphs in the liver and in the male reproductive system

Garnier

Circolo

et al. 2003

Biochemical Journal

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“…Thus, C1r-LP contains the domain corresponding to the Ser proteinase domain of C1r but lacks some of its regulatory parts. It had been noted that C1r-LP lacks an Arg residue at the position where the related Ser proteinases have a site for cleavage͞activation (18). This observation suggests that C1r-LP is active directly after its synthesis and explains why it could cleave proHp in the ER (Fig.…”

Section: Discussionmentioning

confidence: 94%

“…It has been suggested, based on comparison of amino acid sequences, that C1r-LP might not possess proteolytic activity (18). To assess whether proteolytic activity of C1r-LP was responsible for the observed cleavage of proHp, we mutated the conserved Ser residue from the hypothetical active site (Ser-436) to Ala.…”

Section: Resultsmentioning

confidence: 99%

“…Comparison of the genes for C1r and C1r-LP suggests that C1r-LP arose through a duplication of C1r, or of a common ancestral gene, followed by an internal deletion (18). Thus, C1r-LP contains the domain corresponding to the Ser proteinase domain of C1r but lacks some of its regulatory parts.…”

Section: Discussionmentioning

confidence: 99%

“…In the present study, we isolated a proHp-cleaving enzyme from human serum and identified it as the recently discovered complement C1r-like protein (C1r-LP) (18). Through coexpression and RNA interference experiments, we obtained evidence that C1r-LP is a PC that cleaves proHp in the ER of cells of both hepatic and nonhepatic origin.…”

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confidence: 91%

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Prohaptoglobin is proteolytically cleaved in the endoplasmic reticulum by the complement C1r-like protein

Zernicka-Goetz

Fries

2004

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

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Many secretory proteins are synthesized as proforms that become biologically active through a proteolytic cleavage in the trans-Golgi complex or at a later stage in the secretory pathway. Haptoglobin (Hp) is unusual in that it is cleaved in the endoplasmic reticulum before it enters the Golgi. Here, we present evidence that the recently discovered complement C1r-like protein (C1r-LP) mediates this cleavage. C1r-LP has not previously been shown to possess proteolytic activity, despite its homology to trypsin-like Ser proteinases. We demonstrate that coexpression of the proform of Hp (proHp) and C1r-LP in COS-1 cells effected cleavage of proHp in the endoplasmic reticulum. This cleavage depended on proteolytic activity of C1r-LP because mutation of the putative active-site Ser residue abolished the reaction. Furthermore, incubation of affinitypurified C1r-LP and proHp led to the cleavage of the latter protein. ProHp appeared to be cleaved at the expected site because substitution of Gly for Arg-161 blocked the reaction. C1r-LP showed specificity for proHp, in that it did not cleave the proform of complement C1s, a protein similar to Hp particularly around the cleavage site. C1r-LP accounts for at least part of the endogenous proHp-cleavage activity because suppression of the C1r-LP expression by RNA interference reduced the cleavage of proHp by up to 45% in the cells of a human hepatoma cell line (HepG2).

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