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
[21]  
Higgins PJ, 1997, J IMMUNOL, V158, P2872
[22]   Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat [J].
Howard, J ;
Justus, DE ;
Totmenin, AV ;
Shchelkunov, S ;
Kotwal, GJ .
JOURNAL OF LEUKOCYTE BIOLOGY, 1998, 64 (01) :68-71
[23]  
HSI BL, 1988, AM J REPROD IMMUNOL, V18, P21
[24]   Use of site-specific mutagenesis and monoclonal antibodies to map regions of CD46 that interact with measles virus H protein [J].
Hsu, EC ;
Sabatinos, S ;
Hoedemaeker, FJ ;
Rose, DR ;
Richardson, CD .
VIROLOGY, 1999, 258 (02) :314-326
[25]   Artificial mutations and natural variations in the CD46 molecules from human and monkey cells define regions important for measles virus binding [J].
Hsu, EC ;
Dorig, RE ;
Sarangi, F ;
Marcil, A ;
Iorio, C ;
Richardson, CD .
JOURNAL OF VIROLOGY, 1997, 71 (08) :6144-6154
[26]   DIVERSITY OF SITES FOR MEASLES-VIRUS BINDING AND FOR INACTIVATION OF COMPLEMENT C3B AND C4B ON MEMBRANE COFACTOR PROTEIN CD46 [J].
IWATA, K ;
SEYA, T ;
YANAGI, Y ;
PESANDO, JM ;
JOHNSON, PM ;
OKABE, M ;
UEDA, S ;
ARIGA, H ;
NAGASAWA, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (25) :15148-15152
[27]   Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic Neisseria [J].
Kallstrom, H ;
Liszewski, MK ;
Atkinson, JP ;
Jonsson, AB .
MOLECULAR MICROBIOLOGY, 1997, 25 (04) :639-647
[28]   Independently melting modules and highly structured intermodular junctions within complement receptor type 1 [J].
Kirkitadze, MD ;
Krych, M ;
Uhrin, D ;
Dryden, DTF ;
Smith, BO ;
Cooper, A ;
Wang, XF ;
Hauhart, R ;
Atkinson, JP ;
Barlow, PN .
BIOCHEMISTRY, 1999, 38 (22) :7019-7031
[29]   Central modules of the vaccinia virus complement control protein are not in extensive contact [J].
Kirkitadze, MD ;
Henderson, C ;
Price, NC ;
Kelly, SM ;
Mullin, NP ;
Parkinson, J ;
Dryden, DTF ;
Barlow, PN .
BIOCHEMICAL JOURNAL, 1999, 344 :167-175
[30]   Co-operativity between modules within a C3b-binding site of complement receptor type 1 [J].
Kirkitadze, MD ;
Dryden, DTF ;
Kelly, SM ;
Price, NC ;
Wang, X ;
Krych, M ;
Atkinson, JP ;
Barlow, PN .
FEBS LETTERS, 1999, 459 (01) :133-138