A functional model of the human C1 complex

Arlaud, Gérard J.; Colomb, Maurice G.; Gagnon, Jean

doi:10.1016/0167-5699(87)90860-7

Cited by 131 publications

(110 citation statements)

References 40 publications

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“…Furthermore, the current data (10,11,13) are consistent with the hypothesis that the CUB1-EGF moieties of C1r and C1s each contribute ligands for the interaction between the C1s-C1r-C1r-C1s tetramer and C1q sites located in the individual collagen-like stems of the protein (14,15). Based on these and other features, several low resolution models of the C1 complex have been proposed (2,16,17).…”

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confidence: 99%

“…The classical pathway of complement, a major element of innate immunity against pathogens, is triggered by C1, a 790-kDa complex formed from association of a recognition protein C1q with two modular serine proteases, C1r and C1s, that respectively mediate internal activation and proteolytic activity of the complex (1)(2)(3). C1q is a protein with the overall shape of a bouquet of flowers, comprising six heterotrimeric collagenlike triple helices that associate to form a N-terminal "stalk" and then diverge to form individual "stems," each terminating in a C-terminal globular domain (Ref.…”

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confidence: 99%

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X-ray Structure of the Ca2+-binding Interaction Domain of C1s

Gregory

Thielens

Arlaud

et al. 2003

Journal of Biological Chemistry

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C1, the complex that triggers the classical pathway of complement, is assembled from two modular proteases C1r and C1s and a recognition protein C1q. The N-terminal CUB1-EGF segments of C1r and C1s are key elements of the C1 architecture, because they mediate both Ca 2؉ -dependent C1r-C1s association and interaction with C1q. The crystal structure of the interaction domain of C1s has been solved and refined to 1.5 Å resolution. The structure reveals a head-to-tail homodimer involving interactions between the CUB1 module of one monomer and the epidermal growth factor (EGF) module of its counterpart. A Ca 2؉ ion is bound to each EGF module and stabilizes both the intra-and inter-monomer interfaces. Unexpectedly, a second Ca 2؉ ion is bound to the distal end of each CUB1 module, through six ligands contributed by Glu 45 , Asp 53 , Asp 98 , and two water molecules. These acidic residues and Tyr 17 are conserved in approximately two-thirds of the CUB repertoire and define a novel, Ca 2؉ -binding CUB module subset. The C1s structure was used to build a model of the C1r-C1s CUB1-EGF heterodimer, which in C1 connects C1r to C1s and mediates interaction with C1q. A structural model of the C1q/C1r/C1s interface is proposed, where the rod-like collagen triple helix of C1q is accommodated into a groove along the transversal axis of the C1r-C1s heterodimer.

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confidence: 99%

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confidence: 99%

X-ray Structure of the Ca2+-binding Interaction Domain of C1s

Gregory

Thielens

Arlaud

et al. 2003

Journal of Biological Chemistry

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“…This arrangement maximizes the number of identical contact surfaces with C1q, because the C1s-C1r-C1r-C1s tetramer interacts with four collagen-like C1q arms. The Grenoble model (4) assumes that the C1s repenetrates the C1q cone so that the catalytic domains of the C1s zymogen can have access to the catalytic domains of C1r. In this model, the C1s-C1r-C1r-C1s tetramer interacts with only two C1q arms.…”

Section: Figurementioning

confidence: 99%

“…The catalytic unit itself is a tetrameric complex of two different serine protease proenzymes, C1r and C1s (3). Two C1r and two C1s molecules form a calcium-dependent tetramer that associates with C1q to yield the C1 complex (4). The activation of C1 is a multistep process involving recognition of the activator structure by C1q, transferring the activation signal from the C1q heads to the C1s-C1r-C1r-C1s zymogen tetramer, autoactivation of C1r, and subsequent activation of zymogen C1s by the active C1r.…”

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confidence: 99%

The Cleavage of Two C1s Subunits by a Single Active C1r Reveals Substantial Flexibility of the C1s-C1r-C1r-C1s Tetramer in the C1 Complex

Lőrincz

Gál

Dobó

et al. 2000

The Journal of Immunology

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The activation of the C1s-C1r-C1r-C1s tetramer in the C1 complex, which involves the cleavage of an Arg-Ile bond in the catalytic domains of the subcomponents, is a two-step process. First, the autolytic activation of C1r takes place, then activated C1r cleaves zymogen C1s. The Arg463Gln mutant of C1r (C1rQI) is stabilized in the zymogen form. This mutant was used to form a C1q-(C1s-C1rQI-C1r-C1s) heteropentamer to study the relative position of the C1r and C1s subunits in the C1 complex. After triggering the C1 by IgG-Sepharose, both C1s subunits are cleaved by the single proteolytically active C1r subunit in the C1s-C1rQI-C1r-C1s tetramer. This finding indicates that the tetramer is flexible enough to adopt different conformations within the C1 complex during the activation process, enabling the single active C1r to cleave both C1s, the neighboring and the sequentially distant one.

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“…The first component of human complement, C1, is a complex enzyme comprising two serine proteases, Clr and Cls, that are sequentially activated upon binding of C 1 to various activators (for reviews, see [1][2][3]). Proenzyme Cls, a single-chain protein, is converted through cleavage of a single Arg Ile bond into C]-s, the active protease responsible for the enzymic activity of C1, which contains two disulfide-linked chains A and B.…”

Section: Introductionmentioning

confidence: 99%