Monomeric structures of the zymogen and active catalytic domain of complement protease C1r: Further insights into the C1 activation mechanism

被引:47
作者
Budayova-Spano, M
Grabarse, W
Thielens, NM
Hillen, H
Lacroix, M
Schmidt, M
Fontecilla-Camps, JC
Arlaud, GJ
Gaboriaud, C
机构
[1] CEA, LCCP, Inst Biol Struct Jean Pierre Ebel, CNRS, F-38027 Grenoble 1, France
[2] CEA, LEM, Inst Biol Struct Jean Pierre Ebel, CNRS, F-38027 Grenoble 1, France
[3] BASF AG, D-37065 Ludwigshafen, Germany
[4] ABBOTT GmbH, D-37065 Ludwigshafen, Germany
关键词
D O I
10.1016/S0969-2126(02)00881-X
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1509 / 1519
页数:11
相关论文
共 43 条
[1]   A FUNCTIONAL-MODEL OF THE HUMAN C1 COMPLEX - EMERGENCE OF A FUNCTIONAL-MODEL [J].
ARLAUD, GJ ;
COLOMB, MG ;
GAGNON, J .
IMMUNOLOGY TODAY, 1987, 8 (04) :106-111
[2]   Structural biology of C1: dissection of a complex molecular machinery [J].
Arlaud, GJ ;
Gaboriaud, C ;
Thielens, NM ;
Rossi, V ;
Bersch, B ;
Hernandez, JF ;
Fontecilla-Camps, JC .
IMMUNOLOGICAL REVIEWS, 2001, 180 :136-145
[3]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[4]  
Bode W, 1997, THROMB HAEMOSTASIS, V78, P501
[5]   NATURAL PROTEIN PROTEINASE-INHIBITORS AND THEIR INTERACTION WITH PROTEINASES [J].
BODE, W ;
HUBER, R .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1992, 204 (02) :433-451
[6]   FREE R-VALUE - A NOVEL STATISTICAL QUANTITY FOR ASSESSING THE ACCURACY OF CRYSTAL-STRUCTURES [J].
BRUNGER, AT .
NATURE, 1992, 355 (6359) :472-475
[7]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[8]   The crystal structure of the zymogen catalytic domain of complement protease C1r reveals that a disruptive mechanical stress is required to trigger activation of the C1 complex [J].
Budayova-Spano, M ;
Lacroix, M ;
Thielens, NM ;
Arlaud, GJ ;
Fontecilla-Camps, JC ;
Gaboriaud, C .
EMBO JOURNAL, 2002, 21 (03) :231-239
[10]   THE COMPLEMENT-SYSTEM IN XENOTRANSPLANTATION [J].
DALMASSO, AP .
IMMUNOPHARMACOLOGY, 1992, 24 (02) :149-160