title: Monomeric structures of the zymogen and active catalytic domain of complement protease c1r: further insights into the c1 activation mechanism.
abstract: C1r is the serine protease (SP) that mediates autoactivation of C1, the complex that triggers the classical complement pathway. We have determined the crystal structure of two fragments from the human C1r catalytic domain, each encompassing the second complement control protein (CCP2) module and the SP domain. The wild-type species has an active structure, whereas the S637A mutant is a zymogen. The structures reveal a restricted hinge flexibility of the CCP2-SP interface, and both are characterized by the unique alpha-helical conformation of loop E. The zymogen activation domain exhibits high mobility, and the active structure shows a restricted access to most substrate binding subsites. Further implications relevant to the C1r self-activation process are derived from protein-protein interactions in the crystals.
authors.affiliation: LCCP, Institut de Biologie Structurale Jean-Pierre Ebel, CEA-CNRS, 41 rue Jules Horowitz, Grenoble, France.
authors.forename: Monika
authors.initials: M
authors.lastname: Budayova-Spano
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Grabarse
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Thielens
authors.forename: Heinz
authors.initials: H
authors.lastname: Hillen
authors.forename: Monique
authors.initials: M
authors.lastname: Lacroix
authors.forename: Martin
authors.initials: M
authors.lastname: Schmidt
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Fontecilla-Camps
authors.forename: Gérard J
authors.initials: GJ
authors.lastname: Arlaud
authors.forename: Christine
authors.initials: C
authors.lastname: Gaboriaud
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D003167:Complement Activation; D015923:Complement C1r / Q000737:chemistry* / Q000378:metabolism; D004792:Enzyme Precursors / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity
chemical_list: D004792:Enzyme Precursors; D015923:Complement C1r