*Department of Biology and Biotechnology, Worcester Polytechnic Institute;
and
Institute of Molecular Medicine for the Prevention of Human Disease, The University of TexasHouston Health Science Center
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Abstract |
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Introduction |
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Activation of the complement system may occur via three distinct pathways, termed classical, alternative, and mannose-binding lectin (fig. 1
) (Whaley and Schwaeble 1997
; Smith, Azumni, and Nonaka 1999
). Each of the three activation pathways leads to the fusion of multiple proteins into distinct enzymatic complexes termed the C3 convertases, which function to proteolytically cleave C3 into two fragments, C3b and C3a. A large portion of the C3b generated rapidly deposits on the target, and some covalently binds to the C3 convertase itself, resulting in the formation of the C5 convertase. After C3 cleavage, the three pathways converge into the lytic event involving the terminal sequences C5, C6, C7, C8, and C9 and the oligomerization of C9 (membrane attack complex; MAC), which causes the formation of transmembrane channels and cell lysis (reviewed by Müller-Eberhard 1985
).
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In humans, a number of the regulatory proteins (table 1
) are encoded by a cluster of genes located on the long arm of chromosome 1 (1q32). This region is called the regulator of complement activation (RCA) gene cluster (Weis et al. 1987
; Heine-Suñer et al. 1997
). Although the proteins within the RCA family vary in size, they share significant primary amino acid structure similarities. They are organized in tandem structural units termed short consensus repeats (SCRs), which are present in multiple copies in the protein. Each SCR consists of 6070 highly conserved amino acids, including 4 cysteines. The cysteines are disulphide-bonded, holding the SCRs in a rigid triple-loop structure (reviewed by Hourcade, Holers, and Atkinson 1989
).
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In addition to these well-characterized regulatory proteins, the RCA cluster includes other homologous genes that contain tandem SCRs. Such genes code for proteins related to FH (FHR-1, FHR-2, FHR-3, and FHR-4) (Zipfel and Skerka 1994
; Heine-Suñer et al. 1998
) and another FH-like gene (Weiss and Cannich 1998
) which may encode an FH-related protein not yet characterized. Two other RCA genes, CR1-like (CR1L) and MCP-like (MCPL), share a high degree of similarity to CR1 and MCP genes, respectively (Hourcade et al. 1990, 1992
). Although no CR1L or MCPL protein products have yet been confirmed in humans, the CR1L protein has been identified in baboons (Birmingham et al. 1996
). There are two known pseudogenes, C4BPAL1 and C4BPAL2, homologous to the gene encoding for C4bp
(Pardo-Manuel de Villena and Rodríguez de Córdoba 1995
).
RCA genes that encode SCR-containing proteins with functions other than complement regulation have been identified. These proteins are the ß chain of the C4-binding protein (C4bpß) and the b subunit of blood-clotting factor XIII (FXIIIb), both of which participate in coagulation (Chung, Lewis, and Folk 1974
; Pangburn and Müller-Eberhard 1985
; Hillarp and Dahlbäck 1988
). Some human complement proteins containing SCRs do not belong to the RCA group because their genes are not located within the RCA cluster (e.g., Reid and Day 1989
).
The SCRs found in RCA proteins carry a variety of functions, including protein binding and cofactor activity in complement regulation (reviewed by Hourcade, Holers, and Atkinson 1989
; Reid and Day 1989
). These repeats appear to have a very ancient origin. SCR-containing genes sharing sequence similarity with SCR regions of human complement genes have been found in insects (Drosophila), nematodes (Caenorhabditis elegans), and sponges (Geodia cydonium) (Hoshino et al. 1993
; Ainscough et al. 1998
; Blumbach et al. 1998
; Pahler et al. 1998
). However, the function of the products of such genes in complement has not been investigated. The SCRs from different proteins, even occurring in highly divergent animal lineages, contain a number of conserved amino acid residues, which indicates their common evolutionary origin and functional importance. The degree of divergence between individual SCRs is variable, making it possible to use phylogenetic methods to study their evolution (Krushkal, Kemper, and Gigli 1998
).
To date, the species most divergent from humans found to contain a functional protein regulating complement activation is the bony fish barred sand bass, Parablax nebulifer. The sand bass cofactor protein isolated from plasma and by recombinant cDNA expression, SBP1, has functional and structural similarity to both human C4bp and FH. It consists of tandem SCRs, binds to both C4b and C3b, and serves as a cofactor in their enzymatic cleavage by factor I (Kaidoh and Gigli 1987, 1989
; Dahmen et al. 1994
; Kemper, Zipfel, and Gigli 1998
). Sand bass has at least one more SCR-containing gene, and its predicted protein, sand bass cofactor related protein 1 (SBCRP-1), shares structural similarity with SBP1 (Zipfel et al. 1996
).
Because RCA proteins share extensive structural similarity and functional activities, it is important to know how they originated and evolved. Farries and Atkinson (1991)
proposed that the FH, C4bp
, MCP, DAF, and CR1/CR2 lineages have a starlike origin. However, because the RCA family includes a variety of plasma factors and membrane proteins participating in regulation of both the classical and the alternative pathways, these factors may have appeared at different times in evolution. Genes encoding for C3 and factor B proteins, which are involved in the alternative pathway C3 convertase, probably appeared earlier than C4 and C2, which are involved in the classical pathway convertase (Farries and Atkinson 1991
; Seeger, Mayer, and Klein 1996
; Sunyer, Zarkadis, and Lambris 1998
). The complement regulators that interact with them may also have appeared at different times in evolutionary history.
In the present study, we investigated the homology relationships among RCA proteins and their individual SCRs. We also compared how the homology among individual domains of RCA proteins corresponded to their exon/intron structure and functional activity. Based on these comparisons, we discuss the possible evolution of the RCA members.
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Materials and Methods |
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Alignment of Sequences
Since each protein contains multiple repeats homologous to one another, it was not possible to determine a priori how to align the complete protein sequence. We therefore investigated the homology relationships among individual SCRs. The inferred relationships among repeats were used both to analyze the evolutionary relationships among proteins and to compare the sequence similarities with gene structure and functional activities. One hundred thirty-two SCRs from human RCA proteins and their sand bass homologs (table 1 ) were aligned by an automated program, CLUSTAL W, version 1.7 (Thompson, Higgins, and Gibson 1994
), and the resulting alignment was further improved manually.
Inference of Phylogenetic Trees from Individual SCRs
Phylogenetic trees were inferred by the neighbor-joining and parsimony methods. When the trees were inferred by the neighbor-joining method (Saitou and Nei 1987
), we used two approaches to measure amino acid sequence dissimilarity between repeats. One approach took into account multiple amino acid substitutions and variation of substitution rate among sites (Ota and Nei 1994
). We used the value 0.93 of the shape parameter
for the gamma distribution of substitution rate among sites, estimated from SCRs of human C4bp
and FH (Krushkal, Kemper, and Gigli 1998
). The neighbor-joining tree based on corrected distances was inferred with 1,000 bootstrap replications using the computer software NJBOOTAG (modified from program NJBOOTLI; A. Zharkikh, personal communication).
The second approach was to use Dayhoff (1979
, p.348) PAM distances. These distances were employed to infer neighbor-joining trees by programs from the PHYLIP phylogenetic package, version 3.57c (Felsenstein 1989
). The trees were inferred with 500 bootstrap replications with the programs SEQBOOT, PROTDIST, and NEIGHBOR. The consensus of these 500 trees was inferred with the program CONSENSE.
We also inferred phylogenetic trees from 132 SCRs by the equally weighted parsimony method using PAUP*, version 4.0d63 (Swofford 1998
). Due to the large number of sequences, all possible tree rearrangements could not be evaluated under a feasible computer time and memory. We therefore limited the search to five replications, during which over two million possible tree rearrangements were tried. After these rearrangements, 91 trees with the minimal length of 3,871 substitutions were saved, and the majority-rule (50%) consensus of these trees was inferred. Although this consensus tree may not represent the shortest possible tree, it is in good agreement with the trees inferred by the neighbor-joining method, and therefore it may be informative in the analysis of the RCA proteins.
All of the phylogenetic trees were midpoint-rooted with the help of the RETREE program from the PHYLIP package. The trees were presented using the phylogeny drawing program TreeView, versions 1.6.0 and 1.6.1 (Page 1996
).
Inclusion and Exclusion of Indels
The results presented here for the tree inferred by NJBOOTAG using the neighbor-joining method with correction for the variation of substitution rate among sites are based on inclusion of insertions and deletions (indels). In this case, gaps and amino acid substitutions were treated equally. Similar results were also obtained when indel positions were excluded from analysis (data not shown). In the trees inferred by PHYLIP using Dayhoff PAM distances and by PAUP* using parsimony analysis, gaps were considered an unknown state.
Inference of the Summary Tree of Relationships Among the Entire RCA Protein Sequences
The summary tree of relationships among the entire RCA protein sequences was unambiguously deduced from the phylogenetic trees of individual repeats. The summary tree was derived as a majority-rule consensus tree from the subtrees containing individual short consensus repeats. A hypothetical example of such inference is shown in figure 3
. It includes four protein sequences, PA, PB, PC, and PD. PA contains four homologous repeats, while PB, PC, and PD contain three repeats each. A summary tree of relationships among PA, PB, PC, and PD is inferred as a majority-rule consensus tree from the three subtrees (IIII) of the phylogenetic tree that consists of individual repeats (fig. 3A
). For each sequence, a proportion of repeats supporting the summary tree was computed (fig. 3B
).
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Results |
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Figure 4
shows the homology relationships among RCA proteins summarized from all trees inferred, and table 4
indicates that this tree topology is strongly supported by the majority of repeats in each protein. In contrast to the previously proposed scheme of the starlike evolution of RCA members (Farries and Atkinson 1991
), we found that their evolution was not starlike. The observed protein sequence similarities of RCA members mostly correlate with the physical location of the human RCA genes on chromosome 1. Our phylogenetic comparisons indicate the presence of two distinct groups which are known to be separated by a genetic distance of 722.5 cM (Rey-Campos, Rubinstein, and Rodríguez de Córdoba 1988
; Heine-Suñer et al. 1997
). One group (group 1) includes human FH, FH-related proteins FHR-1, FHR-2, FHR-3, and FHR-4, and coagulation factor FXIIIb. Indeed, the genes encoding for these proteins are closely linked and located within 650 kb2.2 Mb (Rey-Campos, Baeza-Sanz, and Rodriguez de Cordoba 1990
; Skerka et al. 1995
; Heine-Suñer et al. 1998
; Weiss and Cannich 1998
). These proteins express the greatest structural similarity to sand bass proteins SBP1 and SBCRP-1.
Group 2 includes the genes located within the 900-kb region which code for proteins C4bp, MCP, DAF, complement receptors CR1 and CR2, and CR1L (Rey-Campos, Baeza-Sanz, and Rodriguez de Cordoba 1990
; Pardo-Manuel de Villena and Rodríguez de Córdoba 1995
). In contrast to the high support shown in tables 2 and 3
for clustering of SCRs within group 1 and group 2 proteins, clustering between repeats from groups 1 and 2 had very low support values (data not shown).
The C4bpß gene does not fall within either group. Although the C4bpß gene is located near the C4bp gene (Pardo-Manuel et al. 1990
), only its SCR 2 shows a close similarity to SCRs from group 2 proteins. It is similar to repeat 30 of CR1, repeat 15 of CR2, and other related repeats from group 2 proteins, all of which are similar to SCR 4 of C4bp
(see below). SCRs 1 and 3 of C4bpß are divergent from those of other RCA proteins.
Relationships Among SCRs of Group 1 Proteins
Comparison of phylogenetic relationships among individual SCRs identified several regions of human FH that are homologous to FH-related proteins FHR-1, FHR-2, FHR-3, and FHR-4, sand bass proteins SBP1 and SBCRP-1, and human coagulation factor FXIIIb (fig. 5
). Based on phylogenetic clustering, we identified four distinct subtypes of SCRs: those similar to (1) repeat 2 of FH, (2) SCRs 69 and related repeat 4, (3) SCRs 1820 of FH and more distantly related repeats 1, 3, 10, and 1416, or (4) SCRs divergent from all three of the above types.
Human FH-related proteins FHR-1, FHR-2, FHR-3, and FHR-4 seem to have diverged very recently from the regions that correspond to SCRs 69 and 1820 of FH. The support for these clusterings was very high, in most cases above 90% (table 2
). These regions are also duplicated in murine FH-related proteins (Zipfel and Skerka 1994
).
Among SCRs of SBP1, repeat 2 seems to be closely related to repeat 2 of FH, and their clustering is supported by 88%100% (table 2 ). SCR 16 is similar to SCR 19 of FH (44%100% support), while repeat 17 is most similar to repeat 20 of FH (86%100% support). Repeat 3 is similar to repeat 10 of FH and distantly related to repeats 1820 of FH. Several other more divergent SCRs of SBP1 were likely to have a common origin with repeats 69 or 1820 of FH (data not shown). SCR 1 is similar to both repeat 1 and repeat 3 of FH. Repeat 4 is similar to both repeat 10 and repeat 20 of factor H, and repeat 6 is similar to repeats 410 and 20 (fig. 5 ).
As noted previously (Zipfel et al. 1996
; Krushkal, Kemper, and Gigli 1998
), sand bass proteins SBCRP-1 and SBP1 diverged very recently (fig. 4
). The three SCRs of SBCRP-1 are closely related to repeats 6, 16, and 17 of SBP1, respectively (82%100% support; table 2
).
Comparison of the SCRs of coagulation factor FXIIIb and FH again shows groups of repeats that are likely to be related to repeats 69 and 1820 of FH (fig. 5 ). SCRs 2 and 3 are likely to have a common origin with repeat 8 of FH, while repeats 8 and 10 clustered with 20 of FH. Repeat 1 is similar to repeats 4 and 69 of FH, and repeats 57 and 9 are related to repeats 1416 of FH (data not shown). Finally, SCR 4 of FXIIIb was clustered with repeats 3, 4, and 69 of FH.
The structural homology among proteins shown in figure 5
is in agreement with the exon/intron structure of their genes. All known functional regulators of complement activation have one or more SCRs encoded by two exons ("split" SCRs), with a splice site after the second nucleotide within the Gly34 codon of the SCR consensus sequence (Hillarp et al. 1993
). In murine FH, SCR 2 is the only repeat encoded by two exons (Vik et al. 1988
). In contrast, sequence similarity in FH-related proteins FHR-1, FHR-2, FHR-3, and FHR-4 and coagulation factor FXIIIb shows the absence of such split SCRs. This observation has been experimentally confirmed for the FHR-2 (Skerka et al. 1995
) and FXIIIb genes (Bottenus, Ichinose, and Davie 1990
).
Relationships Among SCRs of Group 2 Proteins
MCP, DAF, CR1, and CR1L share structural similarity to repeats 14 of C4bp (fig. 6
). Table 3
lists tree nodes with over 50% support for such clustering of SCRs. DAF has a duplication of repeat 1 and lacks repeat 4 of C4bp
. The 30-SCR variant of CR1 has four tandem long homologous repeats (LHRs) similar to one another. Each LHR consists of seven SCRs closely related to SCRs 1, 2, 3, 4, 3, 2, and 3 of C4bp
, respectively. In each LHR, there are three SCRs related to SCR 3 of C4bp
. These repeats are further classified as type a, b, or c according to their degree of similarity (fig. 6
). SCRs 29 and 30 of CR1 are similar to SCRs 3 and 4 of C4bp
. CR1L consists of 7 SCRs, each similar to SCRs within an LHR of CR1, except for SCR 7, which is similar to SCR 2 of both CR1 and C4bp
(table 3
).
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CR2 has a more complex structure. The first 11 SCRs of CR2 are organized in three tandem 4-SCR arrays similar to SCRs 3, 4, 3, and 2 of C4bp, respectively (fig. 6
). In addition, the two pairs of SCRs 12-13 and 14-15 are similar to SCRs 3 and 4 of C4bp
. SCRs 4, 8, and 11 are encoded by two exons each, while SCRs 1-2, 5-6, 9-10, 12-13 and 14-15 are the result of fused exons (Fujisaku et al. 1989
). Similarities between individual repeats of complement receptors CR1 and CR2 (fig. 6
) suggest that the evolution of these proteins was complex and resulted from a number of crossover events. In particular, while SCRs 128 of CR1 are arranged so that SCRs of types a, b, and c (similar to SCR 3 of C4bp
) maintain their position in each LHR, SCRs 29 and 30 of CR1 and SCRs 115 of CR2 show a complex order of occurrence of b and c type repeats.
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Discussion |
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The RCA proteins fall into two distinct groups on the basis of their sequence homology (fig. 4
). This division is independent of the functional activities of the proteins. For example, the two human plasma complement regulators, FH and C4bp, belong to different groups. FH is more closely related to the blood-clotting protein FXIIIb than to many complement regulators such as C4bp
, CR1, MCP, and DAF.
From the sequence data used in this study, it was not possible to reach a conclusion as to when the divergence between the group 1 and group 2 RCA members occurred. Sequence similarity between human factor H, sand bass SBP1, and the C. elegans FH-like protein F36H2.3 suggest that FH, an alternative pathway member, is old in evolutionary history (Krushkal, Kemper, and Gigli 1998
). Although individual repeats of human C4bp
are distinct from those of FH, SBP1 and F36H2.3, as shown by the phylogenetic tree inference, the average amino acid sequence divergence between C4bp
and FH is lower than that between C4bp
and SBP1 (Krushkal, Kemper, and Gigli 1998
). Assuming that SBP1 is the single precursor of both plasma complement regulators, FH and C4bp
, the divergence between FH and C4bp
may have occurred in evolutionary history after the separation of the fish lineage. However, one cannot exclude a possibility that the split between the group 1 and group 2 proteins may have occurred before the appearance of the fish lineage and that a C4bp
-like protein in fish has yet to be identified.
The last four SCRs of C4bp do not have close sequence similarity to SCRs of the group 2 proteins CR1, CR2, CR1L, MCP, or DAF (fig. 6
). They are also divergent from SCRs of the group 1 proteins. There are two possible explanations for their divergent nature. One is that the ancestral precursor of the group 2 proteins was a C4bp
-like molecule that contained eight divergent SCRs. As a result of a series of gene duplications and unequal-crossing-over events, only the first four SCRs were propagated to give rise to MCP, DAF, CR1, CR1L, and CR2. It is also possible that the precursor of the group 2 proteins was an MCP-like molecule with only four SCRs. C4bp
may have appeared after unequal crossing over, resulting in the merging of the four SCRs of such a precursor with the four repeats of some distant SCR-containing protein.
C4bpß is distinct from both groups of the RCA proteins. Its gene may have a mosaic structure, originating as a result of an unequal crossing over between different SCR-containing genes. However, the location of the C4bpß gene within the RCA cluster in tight linkage with the C4bp gene (Pardo-Manuel et al. 1990
), as well as the presence of a split SCR 3 within C4bpß (Hillarp et al. 1993
), suggests a common origin of this gene and other RCA members. Either the C4bpß gene may have appeared very early in the evolution of the RCA cluster or its sequence may have diverged from other RCA members due to diversifying selection.
The evolutionary relationships among individual SCRs may explain the functional similarities and differences expressed by RCA members within groups 1 and 2. SCRs 14 or 15 of FH are necessary for its cofactor and decay accelerating activities (Gordon et al. 1995
; Kuhn and Zipfel 1996
; Sharma and Pangburn 1996
), while C3b binding is mediated by three sites: repeats 14, 610, and 1620 (Sharma and Pangburn 1996
). Since the N-terminal SCRs are not present in the FH-related proteins (fig. 5
), it should be expected that FHR-1, FHR-2, FHR-3, and FHR-4 lack the cofactor activity but can bind C3b. The results of this theoretical analysis are in agreement with published experimental data, which show a lack of cofactor activity in FHR-1 and FHR-2 (Timmann, Leippe, and Horstmann 1991
) and the existence of C3b binding by FHR-4 (Hellwage, Skerka, and Zipfel 1997
).
FH and SBP1 are the only two proteins of group 1 with homology at the N-terminus; however, the functional significance of this structural finding has not yet been elucidated. In agreement with the sequence analysis results, these proteins both display cofactor activity, decay accelerating activity, and C3b binding (Pangburn, Schreiber, and Müller-Eberhard 1977
; Kaidoh and Gigli 1989
). The N-terminal repeats of SBP1 are important for binding and cofactor activity for both human C4b and trout C3b (Kemper, Zipfel, and Gigli 1998
). The observation that SCR 2 of SBP1 is very similar to the split SCR 2 of FH suggests their functional importance.
The functional role of SCRs in the group 2 proteins also correlates with their phylogenetic clustering and shows the importance of the N-terminal repeats, including a split SCR (repeat 2 of C4bp, fig. 6
). Such repeats are essential in the binding of human C4bp
to C4b (Dahlbäck, Smith, and Müller-Eberhard 1983
). In murine C4bp
, the binding activity has been localized to SCRs 13 (Ogata et al. 1993). SCRs 24 of DAF, corresponding to repeats 13 of C4bp
, are functionally important (Coyne et al. 1992
; Brodbeck et al. 1996
). Human CR1 expresses multiple functional sites located in SCRs 14, 810, and 1518, all of which are related to the N-terminal repeats of C4bp
(Klickstein et al. 1988
; Krysch et al. 1994
; Reilly et al. 1994
). Binding of iC3b/C3dg to CR2 is affected by SCRs 1 and 2 (Lowell et al. 1989
; Molina et al. 1995
). All four SCRs of human MCP play a functional role in either cofactor activity or binding of C3b (Adams et al. 1991
; Iwata et al. 1995
). Therefore, similar to group 1 proteins, repeats in group 2 proteins that are related to SCRs 14 of C4bp
often participate in complement regulation, and the split SCR 2 is functionally important in both groups. In addition, the order of repeats also seems to play a role, since other SCRs similar to SCR 2 (split SCRs 6, 13, 20, and 27 of CR1 and 4, 8, and 11 of CR2) are not involved in complement regulation.
In summary, despite the long evolutionary history of the RCA proteins, which originated at least as early as the appearance of bony fish, a remarkable conservation of the N-terminal SCRs is observed within the group 1 and group 2 proteins, which carry a functional activity in complement interactions. Proteins lacking such N-terminal repeats seem to have lost their ability to participate in complement regulation. Future identification and analysis of complement regulators in fish, amphibians, reptiles, and mammals, as well as a detailed study of their more ancient homologs, may provide further insight into the origin and evolution of the group 1 and group 2 proteins.
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Supplementary Material |
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Acknowledgements |
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Footnotes |
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1 Keywords: regulator of complement activation
short consensus repeats
classical pathway
alternative pathway
human
barred sand bass
2 Address for correspondence and reprints: Julia Krushkal, Department of Biology and Biotechnology, Worcester Polytechnic Institute, 100 Institute Road, Worcester, Massachusetts 01609-2280. E-mail: krushkal{at}wpi.edu
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literature cited |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Adams, E. M., M. C. Brown, M. Nunge, M. Krych, and J. P. Atkinson. 1991. Contribution of the repeating domains of membrane cofactor protein (CD46) of the complement system to ligand binding and cofactor activity. J. Immunol. 147:30053011.
Ainscough, R., S. Bardill, K. Barlow et al. (404 co-authors). 1998. Genome sequence of the nematode C. elegans: a platform for investigating biology. Science 282:20122018.
Aso, T., S. Okamura, T. Matsuguchi, N. Sakamoto, T. Sata, and Y. Niho. 1991. Genomic organization of the chain of the human C4b-binding protein gene. Biochem. Biophys. Res. Commun. 174:222227.[ISI][Medline]
Birmingham, D. J., C. M. Logar, X.-P. Shen, and W. Chen. 1996. The baboon erythrocyte complement receptor is a glycophosphatidylinositol-linked protein encoded by a homologue of the human CR1-like genetic element. J. Immunol. 157:25862592.[Abstract]
Blumbach, B., Z. Pancer, B. Diehl-Seifert, R. Steffen, J. Munkner, I. Muller, and W. E. Muller. 1998. The putative sponge aggregation receptor. J. Cell Sci. 111:26352644.
Bottenus, R. E., A. Ichinose, and E. W. Davie. 1990. Nucleotide sequence of the gene for the b subunit of human factor XIII. Biochemistry 29:1119511209.
Brodbeck, W. G., D. Liu, J. Sperry, C. Mold, and M. E. Medof. 1996. Localization of classical and alternative pathway regulatory activity within the decay-accelerating factor. J. Immunol. 156:25282533.[Abstract]
Chung, S. I., M. S. Lewis, and J. E. Folk. 1974. Relationships of the catalytic properties of human plasma and platelet transglutaminases (activated blood coagulation factor XIII) to their subunit structures. J. Biol. Chem. 249:940950.
Coyne, K. E., S. E. Hall, S. Thompson, M. A. Arce, T. Kinoshita, T. Fujita, D. J. Anstee, W. Rosse, and D. M. Lublin. 1992. Mapping of epitopes, glycosylation sites, and complement regulatory domains in human decay accelerating factor. J. Immunol. 149:29062913.
Dahlbäck, B., C. A. Smith, and H. J. Müller-Eberhard. 1983. Visualization of human C4b-binding protein and its complexes with vitamin K-dependent protein S and complement protein C4b. Proc. Natl. Acad. Sci. USA 80:34613465.
Dahmen, A., T. Kaidoh, P. F. Zipfel, and I. Gigli. 1994. Cloning and characterization of a cDNA representing a putative complement-regulatory plasma protein from barred sand bass (Parablax nebulifer). Biochem. J. 301:391397.[ISI][Medline]
Dayhoff, M. O. 1979. Atlas of protein sequence and structure. Vol. 5, Suppl. 3. National Biomedical Research Foundation, Washington, D.C.
Farries, T. C., and J. P. Atkinson. 1991. Evolution of the complement system. Immunol. Today 12:295300.
Fearon, D. T. 1979. Regulation of the amplification C3 convertase of human complement by an inhibitory protein isolated from human erythrocyte membrane. Proc. Natl. Acad. Sci. USA 76:58675871.
Felsenstein, J. 1989. PHYLIPphylogeny inference package (version 3.2). Cladistics 5:164166.
Fujisaku, A., J. B. Harley, M. B. Frank, B. A. Gruner, B. Frazier, and V. M. Holers. 1989. Genomic organization and polymorphisms of the human C3d/Epstein-Barr virus receptor. J. Biol. Chem. 264:21182125.
Fujita, T., T. Inoue, K. Ogawa, K. Iida, and N. Tamura. 1987. The mechanism of action of decay-accelerating factor (DAF). DAF inhibits the assembly of C3 convertases by dissociating C2a and Bb. J. Exp. Med. 166:12211228.[Abstract]
Gigli, I., T. Fujita, and V. Nussenzweig. 1979. Modulation of the classical pathway C3 convertase by plasma proteins C4-binding protein and C3b inactivator. Proc. Natl. Acad. Sci. USA 76:65966600.
Gordon, D. L., R. M. Kaufman, T. K. Blackmore, J. Kwong, and D. M. Lublin. 1995. Identification of complement regulatory domains in human factor H. J. Immunol. 155:348356.[Abstract]
Heine-Suñer, D., M. A. DÍaz-Guillén, F. P.-M. De Villena, M. Robledo, J. BenÍtez, and S. RodrÍguez de Córdoba. 1997. A high-resolution map of the regulator of the complement activation gene cluster on 1q32 that integrates new genes and markers. Immunogenetics 45:422427.
Heine-Suñer, D., M. A. DÍaz-Guillén, P. Sánchez-Corral, and S. RodrÍguez de Córdoba. 1998. An integrated map of the human RCA gene cluster that positions 85 genes and polymorphic markers. Mol. Immunol. 35:395.
Hellwage, J., C. Skerka, and P. F. Zipfel. 1997. Biochemical and functional characterization of the factor-H-related protein 4 (FHR-4). Immunopharmacology 38:149157.
Hillarp, A., and B. Dahlbäck. 1988. Novel subunit in C4b-binding protein required for protein S binding. J. Biol. Chem. 263:1275912764.
Hillarp, A., F. Pardo-Manuel, R. R. Ruiz, S. Rodriguez de Cordoba, and B. Dahlbäck. 1993. The human C4b-binding protein ß-chain gene. J. Biol. Chem. 268:1501715023.
Hoshino, M., F. Matsuzaki, Y.-I. Nabeshima, and C. Hama. 1993. hikaru genki, a CNS-specific gene identified by abnormal locomotion in Drosophila, encodes a novel type of protein. Neuron 10:395407.
Hourcade, D., A. D. Garcia, T. W. Post, P. Taillon-Miller, V. M. Holers, L. M. Wagner, N. S. Bora, and J. P. Atkinson. 1992. Analysis of the human regulators of complement activation (RCA) gene cluster with yeast artificial chromosomes (YACs). Genomics 12:289300.
Hourcade, D., V. M. Holers, and J. P. Atkinson. 1989. The regulators of complement activation (RCA) gene cluster. Adv. Immunol. 45:381416.[ISI][Medline]
Hourcade, D., D. R. Miesner, C. Bee, W. Zeldes, and J. P. Atkinson. 1990. Duplication and divergence of the amino-terminal coding region of the complement receptor 1 (CR1) gene. J. Biol. Chem. 265:974980.
Iida, K., and V. Nussenzweig. 1981. Complement receptor is an inhibitor of the complement cascade. J. Exp. Med. 153:11381150.[Abstract]
Iwata, K., T. Seya, Y. Yanagi, J. M. Pesando, P. M. Johnson, M. Okabe, S. Ueda, H. Ariga, and S. Nagasawa. 1995. Diversity of sites for measles virus binding and for inactivation of complement C3b and C4b on membrane cofactor protein CD46. J. Biol. Chem. 270:1514815152.
Kaidoh, T., and I. Gigli. 1987. Phylogeny of C4b-C3b cleaving activity: similar fragmentation patterns of human C4b and C3b produced by lower animals. J. Immunol. 139:194201.
. 1989. Phylogeny of regulatory proteins of the complement system: isolation and characterization of a C4b/C3b inhibitor and a cofactor from sand bass plasma. J. Immunol. 142:16051613.
Kemper, C., P. F. Zipfel, and I. Gigli. 1998. The complement cofactor protein (SBP1) from the barred sand bass (Paralabrax nebulifer) mediates overlapping regulatory activities of both human C4b binding protein and factor H. J. Biol. Chem. 273:1939819404.
Klickstein, L. B., T. J. Bartow, V. Miletic, L. D. Rabson, J. A. Smith, and D. T. Fearon. 1988. Identification of distinct C3b and C4b recognition sites in the human C3b/C4b receptor (CR1, CD35) by deletion mutagenesis. J. Exp. Med. 168:16991717.[Abstract]
Krushkal, J., C. Kemper, and I. Gigli. 1998. Ancient origin of human complement factor H. J. Mol. Evol. 47:625630.[ISI][Medline]
Krysch, M., L. Clemenza, D. Howdeshell, R. Hauhart, D. Hourcade, and J. P. Atkinson. 1994. Analysis of the functional domains of complement receptor type 1 (C3b/C4b receptor; CD35) by substitution mutagenesis. J. Biol. Chem. 269:1327313278.
Kuhn, S., and P. F. Zipfel. 1996. Mapping of the domains required for decay acceleration activity of the human factor H-like protein 1 and factor H. Eur. J. Immunol. 26:23832387.[ISI][Medline]
Liszewski, K. M., T. W. Post, and J. P. Atkinson. 1991. Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster. Annu. Rev. Immunol. 9:431455.[ISI][Medline]
Lowell, C. A., L. B. Klickstein, R. H. Carter, J. A. Mitchell, D. T. Fearon, and J. M. Ahearn. 1989. Mapping of the Epstein-Barr virus and C3dg binding sites to a common domain on complement receptor type 2. J. Exp. Med. 170:19311946.[Abstract]
Medof, M. E., T. Kinoshita, and V. Nussenzweig. 1984. Inhibition of complement activation on the surface of cells after incorporation of decay-accelerating factor (DAF) into their membranes. J. Exp. Med. 160:15581578.[Abstract]
Misasi, R., H. P. Huemer, W. Schwaeble, E. Sölder, C. Larcher, and M. P. Dierich. 1989. Human complement factor H: an additional gene product of 43 kDa isolated from human plasma shows cofactor activity for the cleavage of the third component of complement. Eur. J. Immunol. 19:17651768.[ISI][Medline]
Molina, H., S. J. Perkins, J. Guthridge, J. Gorka, T. Kinoshita, and V. M. Holers. 1995. Characterization of a complement receptor 2 (CR2, CD21) ligand binding site for C3. An initial model of ligand interaction with two linked short consensus repeat modules. J. Immunol. 154:54265435.
Müller-Eberhard, H. J. 1985. Introduction and overview. Pp. 15 in H. J. Müller-Eberhard and P. A. Miescher, eds. Complement. Springer, Berlin.
Nicholson-Weller, A., J. Burge, D. T. Fearon, P. F. Weller, and K. F. Austen. 1982. Isolation of a human erythrocyte membrane glycoprotein with decay-accelerating activity for C3 convertases of the complement system. J. Immunol. 129:184189.
Ogata, R. T., P. Mathias, B. M. Bradt, and N. R. Cooper. 1993. Murine C4b-binding protein. Mapping of the ligand binding site and the N-termimus of the pre-protein. J. Immunol. 150:22732280.
Ota, T., and M. Nei. 1994. Estimation of the number of amino acid substitutions per site when the substitution rate varies among sites. J. Mol. Evol. 38:642643.[ISI]
Page, R. D. M. 1996. TREEVIEW: an application to display phylogenetic trees on personal computers. Comput. Appl. Biosci. 12:357358.[Medline]
Pahler, S., B. Blumbach, I. Muller, and W. E. Muller. 1998. Putative multiadhesive protein from marine sponge Geodia cydonium: cloning of the cDNA encloding a fibronectin-, and SRCR-, and a complement control protein module. J. Exp. Zool. 282:332343.[ISI][Medline]
Pangburn, M. K., and H. J. Müller-Eberhard. 1985. The alternative pathway of the complement. Pp. 185213 in H. J. Müller-Eberhard and P. A. Miescher, eds. Complement. Springer, Berlin.
Pangburn, M. K., R. D. Schreiber, and H. J. Müller-Eberhard. 1977. Human complement C3b inactivator: isolation, characterization, and demonstration of an absolute requirement for the serum protein ß1H for cleavage of C3b and C4b in solution. J. Exp. Med. 146:257270.[Abstract]
. 1983. Deficiency of an erythrocyte membrane protein with complement regulatory activity in paroxysmal nocturnal hemoglobinuria. Proc. Natl. Acad. Sci. USA 80:54305434.
Pardo-Manuel, F., J. Rey-Campos, A. Hillarp, B. Dahlback, and S. RodrÍguez de Córdoba. 1990. Human genes for the and ß chains of the complement C4b-binding protein are closely linked in head-to-tail arrangement. Proc. Natl. Acad. Sci. USA 87:45294532.
Pardo-Manuel de Villena, F., and S. RodrÍguez de Córdoba. 1995. C4BPAL2: a second duplication of the C4BPA gene in the human RCA gene cluster. Immunogenetics 41:139143.
Post, T. W., M. A. Arce, M. K. Liszewski, E. S. Thompson, J. P. Atkinson, and D. M. Lublin. 1990. Structure of the gene for human complement protein decay accelerating factor. J. Immunol. 144:740744.
Post, T. W., M. K. Liszewski, E. M. Adams, I. Tedja, E. A. Miller, and J. P. Atkinson. 1991. Membrane cofactor protein of the complement system: alternative splicing of serine/threonine/proline-rich exons and cytoplasmic tails produces multiple isoforms that correlate with protein phenotype. J. Exp. Med. 174:93102.[Abstract]
Reid, K. B. M., D. R. Bentley, R. D. Campbell, L. P. Chung, R. B. Sim, T. Krinstensen, and B. F. Tack. 1986. Complement system proteins which interact with C3b or C4b: a superfamily of structurally related proteins. Immunol. Today 7:230234.
Reid, K. B. M., and A. J. Day. 1989. Structure-function relationships of the complement components. Immunol. Today 10:177180.
Reilly, B. D., S. C. Makrides, P. J. Ford, H. C. Marsh Jr., and C. Mold. 1994. Quantitative analysis of C4b dimer binding to distinct sites on the C3b/C4b receptor (CR1). J. Biol. Chem. 269:76967701.
Rey-Campos, J., D. Baeza-Sanz, and S. RodrÍguez de Cordoba. 1990. Physical linkage of the human genes coding for complement factor H and coagulation factor XIII B subunit. Genomics 7:644646.
Rey-Campos, J., P. Rubinstein, and S. RodrÍguez de Córdoba. 1988. A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP. J. Exp. Med. 167:664669.
Rodriguez de Cordoba, S., P. Sanchez-Corral, and J. Rey-Campos. 1991. Structure of the gene coding for the alpha polypeptide chain of the human complement component C4b-binding protein. J. Exp. Med. 173:10731082.[Abstract]
Ross, G. D., M. J. Polley, E. M. Rabellino, and H. M. Grey. 1973. Two different receptors on human lymphocytes: one specific for C3b and one specific for C3b inactivator-cleaved C3b. J. Exp. Med. 138:798811.[ISI][Medline]
Saitou, N., and M. Nei. 1987. The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol. Biol. Evol. 4:406425.[Abstract]
Seeger, A., W. E. Mayer, and J. Klein. 1996. A complement factor B-like cDNA from zebrafish (Brachydanio rerio). Mol. Immunol. 33:511520.[ISI][Medline]
Seya, T., and J. P. Atkinson. 1989. Functional properties of membrane cofactor protein of complement. Biochem. J. 264:581588.[ISI][Medline]
Sharma, A. K., and M. K. Pangburn. 1996. Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis. Proc. Natl. Acad. Sci. USA 93:1099611001.
Skerka, C., J. M. Moulds, P. Taillon-Miller, D. Hourcade, and P. F. Zipfel. 1995. The human factor H-related gene 2 (FHR2): structure and linkage to the coagulation factor XIIIb gene. Immunogenetics 42:268274.
Smith, L. C., K. Azumni, and M. Nonaka. 1999. Complement systems in invertebrates: the ancient alternative and lectin pathways. Immunopharmacology 42:107120.
Sunyer, J. O., I. K. Zarkadis, and J. D. Lambris. 1998. Complement diversity: a mechanism for generating immune diversity? Immunol. Today 19:519523.
Swofford, D. L. 1998. Swofford: PAUP* 4.0 BETA for Windows. Sinauer, Sunderland, Mass.
Thompson, J. D., D. G. Higgins, and T. J. Gibson. 1994. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position specific gap penalties and weight matrix choice. Nucleic Acids. Res. 22:46734680.[Abstract]
Timmann, C., M. Leippe, and R. D. Horstmann. 1991. Two major serum components antigenically related to complement factor H are different glycosylation forms of a single protein with no factor H-like complement regulatory functions. J. Immunol. 146:12651270.
Turner, J. R. 1984. Structural and functional studies of the C3b and C4b binding proteins of a human monocyte-like cell line (U937). Masters thesis, Washington University, St. Louis, Mo.
Vik, D. P., J. B. Keeney, P. Munoz-Canovez, D. D. Chaplin, and B. F. Tack. 1988. Structure of the murine complement factor H gene. J. Biol. Chem. 263:1672016724.
Vik, D. P., and W. W. Wong. 1993. Structure of the gene for the F allele of complement receptor type 1 and sequence of the coding region unique to the S allele. J. Immunol. 151:62146224.
Weigle, W. O., M. G. Goodman, E. L. Morgan, and T. H. Hugli. 1985. Regulation of immune response by components of the complement cascade and their activated fragments. Pp. 323344 in H. J. Müller-Eberhard and P. A. Miescher, eds. Complement. Springer, Berlin.
Weis, J. H., C. C. Morton, G. A. P. Bruns, J. J. Weis, L. B. Klickstein, W. W. Wong, and D. T. Fearon. 1987. A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein Barr virus receptor map to 1q32. J. Immunol. 138:312315.
Weiss, E. H., and A. Cannich. 1998. The genomic organization of the human factor H gene family. Mol. Immunol. 35:411.
Whaley, K., and S. Ruddy. 1976. Modulation of C3b hemolytic activity by a plasma protein distinct from C3b inactivator. Science 193:10111013.
Whaley, K., and W. Schwaeble. 1997. Complement and complement deficiencies. Semin. Liver Dis. 17:297310.[Medline]
Zipfel, P. F., C. Kemper, A. Dahmen, and I. Gigli. 1996. Cloning and recombinant expression of a barred sand bass (Parablax nebulifer) cDNA: the encoded protein displays structural homology and immunological crossreactivity to human complement/cofactor related plasma proteins. Dev. Comp. Immunol. 20:407416.[ISI][Medline]
Zipfel, P. F., and C. Skerka. 1994. Complement factor H and related proteins: an expanding family of complement-regulatory proteins? Immunol. Today 3:121126.