Dissecting sites important for complement regulatory activity in membrane cofactor protein (MCP; CD46)

被引:123
作者
Liszewski, MK
Leung, M
Cui, WY
Subramanian, VB
Parkinson, J
Barlow, PN
Manchester, M
Atkinson, JP
机构
[1] Washington Univ, Sch Med, Div Rheumatol, Dept Med, St Louis, MO 63110 USA
[2] Scripps Res Inst, Dept Neuropharmacol, Div Virol, La Jolla, CA 92037 USA
[3] Edinburgh Ctr Prot Technol, Edinburgh EH9 3JJ, Midlothian, Scotland
关键词
D O I
10.1074/jbc.M004650200
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
Membrane cofactor protein (MCP; CD46), a widely distributed regulator of complement activation, is a cofactor for the factor I-mediated degradation of C3b and C4b deposited on host cells. MCP possesses four extracellular, contiguous complement control protein modules (CCPs) important for this inhibitory activity. The goal of the present study was to delineate functional sites within these modules. We employed multiple approaches including mutagenesis, epitope mapping, and comparisons to primate MCP to make the following observations. First, functional sites were located to each of the four CCPs. Second, some residues were important for both C3b and C4b interactions while others were specific for one or the other. Third, while a reduction in ligand binding was invariably accompanied by a parallel reduction in cofactor activity (CA), other mutants lost or had reduced CA but retained ligand binding. Fourth, two C4b-regulatory domains overlapped measles virus interactive regions, indicating that the hemagglutinin docks to a site important for complement inhibition. Fifth, several MCP regulatory areas corresponded to functionally critical, homologous positions in other CCP-bearing C3b/C4b-binding proteins. Based on these data and the recently derived crystal structure of repeats one and two, computer modeling was employed to predict MCP structure and examine active sites.
引用
收藏
页码:37692 / 37701
页数:10
相关论文
共 68 条
[31]  
Kirkitadze MD, 1999, PROG COLL POL SCI S, V113, P164
[32]   Possible association of infertility with sperm-specific abnormality of CD46 [J].
Kitamura, M ;
Matsumiya, K ;
Yamanaka, M ;
Takahara, S ;
Hara, T ;
Matsumoto, M ;
Namiki, M ;
Okuyama, A ;
Seya, T .
JOURNAL OF REPRODUCTIVE IMMUNOLOGY, 1997, 33 (01) :83-88
[33]   MOLSCRIPT - A PROGRAM TO PRODUCE BOTH DETAILED AND SCHEMATIC PLOTS OF PROTEIN STRUCTURES [J].
KRAULIS, PJ .
JOURNAL OF APPLIED CRYSTALLOGRAPHY, 1991, 24 :946-950
[34]   Structure-function analysis of the active sites of complement receptor type 1 [J].
Krych, M ;
Hauhart, R ;
Atkinson, JP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (15) :8623-8629
[35]   Decay accelerating activity of complement receptor type 1 (CD35) - Two active sites are required for dissociating C5 convertases [J].
Krych-Goldberg, M ;
Hauhart, RE ;
Subramanian, VB ;
Yurcisin, BM ;
Crimmins, DL ;
Hourcade, DE ;
Atkinson, JP .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (44) :31160-31168
[36]  
Lambris JD, 1996, J IMMUNOL, V156, P4821
[37]  
Liszewski MK, 1996, ADV IMMUNOL, V61, P201
[38]  
Liszewski MK, 1998, J IMMUNOL, V161, P3711
[39]  
Liszewski MK, 1996, J IMMUNOL, V156, P4415
[40]  
LISZEWSKI MK, 1998, COMPLEMENT SYSTEM, P146