Crystal structure of the catalytic domain of human complement c1s: a serine protease with a handle.
C1s is the highly specific modular serine protease that mediates the proteolytic activity of the C1 complex and thereby triggers activation of the complement cascade. The crystal structure of a catalytic fragment from human C1s comprising the second complement control protein (CCP2) module and the chymotrypsin-like serine protease (SP) domain has been determined and refined to 1.7 A resolution. In the areas surrounding the active site, the SP structure reveals a restricted access to subsidiary substrate binding sites that could be responsible for the narrow specificity of C1s. The ellipsoidal CCP2 module is oriented perpendicularly to the surface of the SP domain. This arrangement is maintained through a rigid module-domain interface involving intertwined proline- and tyrosine-rich polypeptide segments. The relative orientation of SP and CCP2 is consistent with the fact that the latter provides additional substrate recognition sites for the C4 substrate. This structure provides a first example of a CCP-SP assembly that is conserved in diverse extracellular proteins. Its implications in the activation mechanism of C1 are discussed.
Gaboriaud
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LCCP and LEM, Institut de Biologie Structurale J.-P.EbelCEA-CNRS, 41, rue Jules Horowitz, 38027 Grenoble Cedex 1, France. chris@lccp.ibs.fr
Rossi
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V
Bally
I
I
Arlaud
G J
GJ
Fontecilla-Camps
J C
JC
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D002918:Chymotrypsin / Q000737:chemistry; D003173:Complement C1s / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry*; D013379:Substrate Specificity; D014357:Trypsin / Q000737:chemistry
D011994:Recombinant Proteins; D012697:Serine Endopeptidases; D002918:Chymotrypsin; D014357:Trypsin; D003173:Complement C1s