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*
Department of Biochemistry, Fukushima Medical College, 1-Hikarigaoka, Fukushima, Japan;
Department of Fisheries Science, Kyusyu University, Hakozaki, Fukuoka, Japan;
Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Hachioji, Japan; and
§
Department of Biochemistry, Nagoya City University Medical School, Mizuho-ku, Nagoya, Japan
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Recently, a second form of human MASP (MASP2) was cloned (3), which is
41% identical to and has the same domain structure as the first
form of MASP (MASP1) cloned by us. The precise composition and
stoichiometry of MBL/MASP1/MASP2 complexes, as well as the enzymatic
properties of the two MASPs, are unknown. The overall structures of the
two human MASPs resemble the proteolytic components, human C1r and C1s,
of the C1 complex in the classical complement pathway (2, 3, 7, 8).
Thus, at least four MASP-related molecules, two MASPs, C1r and C1s, are
present in human and are encoded by four different genes. The
MASP/C1r/C1s family forms a unique branch of the serine protease
superfamily, which includes members with a single exon-encoded protease
domain.
It is of considerable interest to determine whether lower animals, especially the lamprey, one of the most primitive vertebrates, have a lectin pathway driven by MASP-like serine protease(s), since the genes encoding several molecules involved in adaptive immunity, such as Ig (9), TCR (10), and MHC class I (11) and II (12), can all be traced back to cartilaginous fish, but not to cyclostomes.
In this paper, we describe the cDNA cloning of six MASPs from vertebrates such as mammals (mouse), amphibians (Xenopus), bony fish (carp), cartilaginous fish (shark), and cyclostomes (lamprey) and discuss the molecular evolution of the MASP/C1r/C1s family including two ascidian MASPs reported recently (13). We also discuss the possible presence of a lectin pathway in these vertebrates.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Xenopus laevis was purchased from Nippon Bio-Supp. Center (Nagoya, Japan). Carp (Cyprinus carpio), shark (Triakia scyllium), and lamprey (Lampetra japonica) were obtained from local dealers in Fukuoka, Mie, and Fukushima, Japan, respectively. Solitary ascidian, Halocynthia roretzi, was harvested in Mutsu Bay, Japan.
Restriction enzymes were purchased from Toyobo (Osaka, Japan) and
Boehringer Mannheim (Mannheim, Germany).
[
-32P]dCTP and the Megaprime DNA labeling system were
from Amersham Japan (Tokyo). The ligation kit was from Takara Shuzo
(Kyoto, Japan). The pGEM-T vector and 
ZAP II were from Promega
(Madison, WI) and Stratagene (La Jolla, CA), respectively.
Nucleotide sequence analysis
DNA sequence was determined by the dideoxy chain termination method (14) using a DNA sequencer (Model 4000; LI-COR, Lincoln, NE). The labeling reaction was conducted using the SequiTherm Long-Read cycle sequencing kit (Epicentre Technologies, Madison, WI). Sequencing primers were synthesized by Nisinbo (Tokyo).
Cloning of MASP cDNAs
RNA was isolated from liver using the acid guanidine
thiocyanate method (15), and the poly(A)+ fraction was
purified by passage through an oligo(dT)-cellulose column (Clontech,
Palo Alto, CA). The liver cDNAs and the cDNA libraries in ZAP
II were prepared as described (16, 17).
A partial cDNA sequence of the mouse counterpart (muMASP2) of human MASP2 (huMASP2) was first obtained from the mouse expression sequence tags (EST) gene bank library (GenBank) by a homology search with the huMASP2 cDNA sequence (3). To complete the 5' coding sequence, a 5' RACE (rapid amplification of cDNA end) was conducted using a kit (Marathon; Clontech) with mouse liver cDNA as a template.
The cDNA of the Xenopus homologue (xeMASP1) of human MASP1 (huMASP1) was cloned by screening a Xenopus liver cDNA library with a 32P-labeled cDNA fragment of huMASP1 (2.8-kbp of EcoRI fragment; 2 as a probe. A positive clone, X43, was subcloned in pBluescript II SK by in vivo excision according to the manufacturer’s instructions (Stratagene), then further subcloned into pBluescript II KS at internal restriction sites and sequenced. 5' RACE and 3' RACE were performed to complete the cDNA sequence.
The cDNA of the Xenopus homologue (xeMASP2) of huMASP2 was amplified by RT-PCR with degenerated primers derived from the conserved amino acid sequences in huMASP1, mouse MASP1 (muMASP1; mouse P-100 in 8 and xeMASP1: IKLYFMH (YF1, 5'-ATIAAA/GCTITAT/CTTT/CATGCA-3', where I represents inosine); YLCEYDY (YF2, 5'-TAT/CCTITGT/CGAA/GTAT/CGAT/CTA-3'), CGEKSP (YR1, 5'-GGIG/CA/T/CT/CTTT/CTCICCA/GCA-3'); and CPYDYL/IK (YR2, 5'-TTIAG/TA/GTAA/GTCA/GTAIGGA/GCA-3'). The PCR products with the expected sizes were cloned into pGEM-T vector and sequenced. A Xenopus liver cDNA library was then screened using the insert DNA as a probe, and positive clones (X112 and X161) were sequenced.
A nested RT-PCR with the same degenerated primers was performed to isolate carp MASP (caMASP) cDNA. Carp liver cDNA library was then screened using the 32P-labeled PCR product as a probe. A positive clone, 2A6, was subcloned and sequenced. A 5' RACE was conducted to complete the 5' coding sequence.
Shark MASP (shMASP) cDNA was isolated by a similar RT-PCR. 5' RACE and 3' RACE were then conducted with the primers corresponding to the nucleotide sequence of the PCR product and shark liver cDNA as a template. All of the sequences of the PCR and 5'/3' RACE products were determined by sequencing three or more clones to rule out PCR error.
A similar RT-PCR was employed to amplify a portion of lamprey MASP (laMASP) cDNA. A lamprey liver cDNA library was then screened with the 32P-labeled PCR product as a probe. Three positive clones, L402, L410, and L412, were subcloned and sequenced.
Cloning of genomic DNA of the huMASP1 and human C1s genes
To determine the exon-intron structure of the huMASP1 gene, the
genomic DNA was cloned by screening EMBL-3 (Clontech) and FIX II
phage libraries (Stratagene) with a 32P-labeled full length
of huMASP1 cDNA (2) as a probe. The overlapping clones (F419, F302,
F210, F301, F21, and A1) were subjected to restriction mapping,
Southern blot hybridization with 32P-labeled fragment of
huMASP1 cDNA, and subcloning at the internal restriction sites and then
sequenced.
The human C1s (huC1s) gene was analyzed by PCR using the sequences of huC1s cDNA as primers and the genomic DNA from human peripheral mononuclear cells as a template. To design primer sequences, the putative positions of intron insertion in the huC1s gene were estimated by referring to those in the huMASP1 gene. The PCR products obtained were cloned in pGEM-T vector and sequenced.
PCR to amplify the gene encoding the protease domain of MASP
Genomic DNA was prepared as described (18). To determine whether the protease domain of each MASP is encoded by a single exon or by split exons, PCR was performed using the genomic DNA as a template. A primer set was designed to amplify the entire protease domain: 5'-TTTGTGGACTATCAGCCCGCACAAC-3' and 5'-CCTTGAGTCAATGGGTAAGGCTGGA-3' for huMASP2; 5'-TTTCCAGGTCTGCTCTAGCAAGA-3' and 5'-AGACACTGGGCTGTCACTTCTAC-3' for xeMASP1; 5'-AGCAGTAGCTCGCGCACGTATAG-3' and 5'-AGTCAGTAATATGTATTTCCATATCA-3' for xeMASP2; 5'-TCTGTGGAAGGCCTGCTCGACC-3' and 5'-ATGTTCAATCAGCAGGATCCTTGC-3' for shMASP; 5'-GCCCAAGCACGTGATAATGGAGTTG-3' and 5'-ACTGACAAACGCGCGTCGTGATCG-3' for laMASP; 5'-GAAGAAGCTCTACAACGATCCTGC-3' and 5'-ACAAAGCGGGTCATTCAATCCAGG-3' for ascidian MASPa (asMASPa; 13 ; and 5'-AGCCGAAGACAATCCACTACTGGC-3' and 5'-ATGATCCATTCAACGACTGTTTGC-3' for asMASPb. The PCR product was visualized on an agarose gel following electrophoresis by staining with ethidium bromide.
Construction of phylogenetic tree
The 14 members of the MASP/C1r/C1s family including huMASP1 (2, 7), huMASP2 (3), muMASP1 (8), muMASP2, xeMASP1, xeMASP2, caMASP, shMASP, laMASP, asMASPa and -b (13), huC1r (19, 20), huC1s (21, 22), and golden hamster C1s (ghC1s; CASP in 23 were aligned at the primary structure level using Clustal w software (EMBL Data Library, Heidelberg, Germany). A pairwise distance matrix was obtained by calculating the proportion of the different amino acids. The matrix was then used to construct trees by the neighbor-joining method (24). Bootstrap analysis was used to assess the reliability of branching patterns. For each tree, 1000 bootstrap replications were performed.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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The cDNAs we obtained of muMASP2, xeMASP1 and -2, caMASP, shMASP,
and laMASP encoded 685, 698, 688, 745, 720, and 722 amino acids,
respectively. An alignment was made of the amino acid sequences of
these proteins in addition to those of huMASP1 and -2 and
muMASP1 (Fig. 1
). All of the deduced
amino acid sequences consisted of putative signal peptides followed by
the secreted proenzyme forms of MASP. The latter consisted of six
domains, which are also conserved in the previously cloned members of
the MASP/C1r/C1s family. Three amino acid residues (His489,
Asp551, and Ser645, numbering in xeMASP1)
essential for the active center of serine protease (25) and the
proteolytic cleavage site between Arg446 and
Ile447, essential for generating the active form of MASP
comprising two polypeptides (heavy and light chains), were also
conserved. All members have an aspartic acid residue at -6 relative to
the active site serine, a substrate-related residue (25),
suggesting their trypsin-type substrate specificity.
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The calculated percentages of identity of each MASP to other members at
the amino acid sequence level are shown in Figure 2. The high percentages of identity of
huMASP1 vs muMASP1 and huMASP2 vs muMASP2 strongly suggest that muMASP1
and -2 are mouse counterparts of huMASP1 and -2, respectively. The
significantly higher percentages of identity of xeMASP1 vs huMASP1 and
xeMASP2 vs huMASP2 also indicate that xeMASP1 and -2 are
Xenopus counterparts of huMASP1 and -2, respectively. Both
caMASP and shMASP have slightly higher percentages of identity to the
MASP1 group rather than to the MASP2 group, although the structural
features of their protease domains, such as the absence of the
histidine loop disulfide bridge and an AGY codon at the active site
serine, are commonly shared with the MASP2 group. This suggests that
the evolutionary history of MASP is not simple and that both caMASP and
shMASP are direct counterparts of neither MASP1 nor MASP2 (see below).
The laMASP showed 36.6 to 41.3% identity with other vertebrate
MASPs and 37.3 to 37.5% with huC1r/C1s, respectively. This
result, together with an apparent lack of the classical complement
pathway in the lamprey (27), suggests that the divergence of
cyclostomes predated the gene duplication between MASP and C1r/C1s.
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The presence of transcripts in liver corresponding to the above cDNAs was confirmed by Northern blot hybridization for liver mRNA using our cDNAs as probes: 3.6-, 2.7-, and 1.2-kb-long transcripts of muMASP2; 5.0 and 2.6 kb of xeMASP1; 2.9 and 1.2 kb of xeMASP2; 4.7, 3.0, and 1.7 kb of caMASP; 4.0, 2.9, 2.3, and 1.8 kb of shMASP; and 5.0, 3.1, and 1.0 kb of laMASP (data not shown).
Exon-intron structures of the huMASP1 and huC1s genes
The entire huMASP1 gene spans more than 50 kbp and contains at
least 16 exons (Fig. 3). The first
internal repeat, epidermal growth factor (EGF)-like, the second
internal repeat, and the first and the second short consensus repeat
(SCR) domains are encoded by 2, 1, 2, 2, and 2 exons, respectively. As
reported previously (28), the protease domain of huMASP1 is encoded by
six exons. All of the splice acceptor and donor sequences were
consistent with the AG/GT rule.
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13 kbp and contains 12 exons
(Fig. 3
). Compared with the huMASP1 gene, the huC1s gene is very
compact owing to the short introns. It was also found that the
positions of introns were completely conserved between the huMASP1 and
the huC1s genes throughout the regions encoding the heavy chain (five
N-terminal domains). As reported by Tosi et al. (29), the protease
domain of huC1s is uniquely encoded by a single exon, as is huC1r (28, 29). Interestingly, the position of the intron in the N-terminal region
of the protease domain is also conserved between the two genes, where
both Val435 of huMASP1 and the homologous
Val409 of C1s are interrupted by the introns at phase 1.
These results clearly suggest that the MASP/C1r/C1s family was
essentially generated from a common ancestor, regardless of the
structural difference in their protease domains. Exon organization of the region encoding the protease domain of MASPs
As shown in Figure 4, PCR
amplification of the genomic regions encoding the protease domains of
huMASP2, xeMASP2, caMASP, shMASP, and laMASP resulted in products with
the same sizes as those obtained by PCR with the respective cDNAs as
templates. This suggests that their protease domains are encoded by an
intronless exon. In contrast, PCR amplification of the region encoding
the protease domain of xeMASP1 resulted in no product with the same
size as that from a similar PCR with the cDNA as a template, suggesting
that the protease domain of xeMASP1 is encoded by multiple exons. These
results clearly demonstrate that two lineages of the MASP genes are
present in vertebrates.
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),
suggesting that the protease domains of these MASPs are encoded by
multiple exons. By a preliminary sequencing of the PCR products, the
protease domains of asMASPa and -b were found to be encoded by at least
seven and five exons, respectively (data not shown). Two of all of the
positions of introns were conserved between asMASPa and -b genes. One
of the two was quite similar to the most downstream position of intron
of the huMASP1 gene. Phylogeny of the MASP/C1r/C1s family
A phylogenetic tree constructed based on the alignment of the
entire amino acid sequences shows that caMASP and shMASP formed a
branch together with the MASP1 group (Fig. 5A). The high percentages of
bootstrap analysis support this branching. A phylogenetic tree based on
the regional sequences of the heavy chains show essentially the same
branching pattern (data not shown). As shown in Figure 5B,
however, another phylogenetic tree based on the regional amino acid
sequences of the protease domains show that these two MASPs form a
unique branch together with the laMASP, MASP2, and C1r/C1s groups.
Although bootstrap values supporting this branching pattern are not
fully convincing, these results may suggest that the heavy and light
chain domains of MASP followed separate evolutionary pathways (see
below).
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B suggests that a single evolutionary event before
the emergence of primitive vertebrates may have generated two lineages.
One is the MASP1 group, termed the TCN type, which possesses a set of
structural features such as the presence of the histidine loop in the
protease domain, TCN codon at active site serine, a proline residue at
position 3 relative to the active site serine, and split exons for the
protease domain. Another group could include MASP2, caMASP, shMASP,
laMASP, and huC1r/C1s. This group, termed the AGY type, is
characterized by the absence of the histidine loop, an AGY codon at the
active site serine, an alanine or valine residue at position 3 relative
to the serine, and a single exon for the protease domain. Accumulating
evidence seems to support the notion that the TCN type is a prototype
of the MASP/C1r/C1s family. TCN-type MASP possesses a histidine loop,
which is seen in most serine proteases, regardless of whether they are
TCN type or AGY type, including digestive enzymes, blood coagulation
factors, and complement serine proteases such as factor B (16, 17, 30). Furthermore, the AGY codon for the active site serine was
reportedly found only in the serine protease genes of vertebrates (31, 32). Actually, the active site serines of asMASPa and -b are encoded by
the TCG and TCT codon (13), respectively. The proline residue at
position 3 relative to the active site serine is conserved in most of
the above-mentioned serine proteases. Proline in laMASP is the only
exception, suggesting that it contains an ancient form of the AGY type. The question arises as to whether the lower vertebrates such as carp, shark, and lamprey have a TCN-type MASP. To date, our repeated attempts using PCR with a variety of primers have failed to isolate such a clone from liver cDNA in these species. A plausible explanation is that although the expected genes are present in the genomes of these species, they are silent or at least not expressed in liver.
Figure 6 shows a possible mechanism for
generating an AGY-type MASP/C1r/C1s from a prototype of TCN-type MASP.
Before the emergence of vertebrates, retroposition of the TCN-type MASP
gene and base changes from TCN to AGY at the active site serine would
generate a prototype of the AGY-type MASP gene. A partially processed
mRNA (33) consisting of an unprocessed sequence for heavy chain and a
precisely processed sequence for light chain (protease domain) would be
transpositioned. A similar retroposition event was reported in the
generation of the preproinsulin I gene from the preproinsulin II gene
(34). Owing to generation of the AGY-type MASP gene, the TCN-type MASP
gene might have become a silent gene in primitive vertebrates. At the
evolutionary stage between cyclostomes and cartilaginous fish, the
AGY-type MASP gene might have doubled by gene duplication to produce a
prototype of the C1r/C1s genes. Jensen et al. have presented evidence
for the classical pathway in nurse shark, a cartilaginous fish,
comprising six complement components (35). One of the six, termed C1n,
is thought to be equivalent to mammalian C1 complex, the structure of
which remains to be elucidated. Before the divergence of amphibians, a
gene conversion event could have replaced the region of the AGY-type
MASP gene containing the promoter and the region for the heavy chain
with the homologous region of a silent TCN-type gene, bringing about a
MASP1 gene. At this stage, the AGY-type MASP gene could have changed
rapidly, in turn, to MASP2 to share the function with MASP1.
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The presence of MASPs in all of the species analyzed in this study strongly suggests that the lectin pathway functions extensively in the vertebrate line. The structural similarity between shMASP and caMASP suggests that cartilaginous fish, bony fish, and probably cyclostomes may have lectin pathway similar to each other, which is slightly different from that in mammals and amphibians. At the stage of amphibian evolution, the lectin pathway may have developed to such a point that two the MASPs, MASP1 and MASP2, function cooperatively in a complex. The presence of the two types of MASP in mammals, amphibians, and ascidians, regardless of the structural difference in the protease domains, leads us to speculate that these two MASPs have distinct functions. It was reported that huMASP1 cleaves C3, whereas huMASP2 cleaves C4 (3). The difference in the specificity of the substrate molecule between huMASP1 and -2 seems to be due to structural differences in the heavy chains, especially in the SCR domains (36) of both proteins. It is likely that the MASPs in lower vertebrates activate C3-like molecules as does MASP1, because their heavy chains are closely related to those of MASP1. Further studies of MASP proteins will clarify the mechanisms underlying the lectin pathway in these vertebrates.
In conclusion, the present phylogenetic analysis of the MASP/C1r/C1s family has revealed the presence of two different lineages of the MASP gene in vertebrates and suggests that one of the two, a unique lineage with a single exon-encoded protease domain, may have diverged from a common ancestor before the emergence of vertebrates. Compared with the origin of the classical complement pathway at the stage of cartilaginous fish (35, 37, 38), the lectin pathway seems to have a more ancient origin.
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Acknowledgments |
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Footnotes |
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2 The nucleotide sequence data reported in this paper will appear in the DDBJ, EMBL, and GenBank nucleotide sequence databases with the following accession numbers: AB009459 for muMASP2 cDNA, D83276 for xeMASP1 cDNA, AB009072 for xeMASP2 cDNA, AB009073 for caMASP cDNA, AB009074 for shMASP cDNA, AB009075 for laMASP cDNA, AB10813–22 for huMASP1 genomic DNAs, and AB009076 for huC1s genomic DNA.
3 Address correspondence and reprint requests to Dr. Yuichi Endo, Department of Biochemistry, Fukushima Medical College, 1-Hikarigaoka, Fukushima 960-1295, Japan.
4 Abbreviations used in this paper: MBL, mannose-binding lectin; MASP, MBL-associated serine protease; mu/hu/ca/sh/la/xe/asMASP, mouse/human/carp/shark/lamprey/Xenopus/ascidian MASP; RACE, rapid amplification of cDNA end; SCR, short consensus repeat.
Received for publication March 23, 1998. Accepted for publication June 22, 1998.
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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C. M. Stover, S. Thiel, M. Thelen, N. J. Lynch, T. Vorup-Jensen, J. C. Jensenius, and W. J. Schwaeble Two Constituents of the Initiation Complex of the Mannan-Binding Lectin Activation Pathway of Complement Are Encoded by a Single Structural Gene J. Immunol., March 15, 1999; 162(6): 3481 - 3490. [Abstract] [Full Text] [PDF]
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Y. Endo, K. Kanno, M. Takahashi, K.-i. Yamaguchi, Y. Kohno, and T. Fujita Molecular Basis of Human Complement C1s Deficiency J. Immunol., February 15, 1999; 162(4): 2180 - 2183. [Abstract] [Full Text] [PDF]
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 R. Wallis and R. B. Dodd Interaction of Mannose-binding Protein with Associated Serine Proteases. EFFECTS OF NATURALLY OCCURRING MUTATIONS J. Biol. Chem., September 29, 2000; 275(40): 30962 - 30969. [Abstract] [Full Text] [PDF]
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A. Kenjo, M. Takahashi, M. Matsushita, Y. Endo, M. Nakata, T. Mizuochi, and T. Fujita Cloning and Characterization of Novel Ficolins from the Solitary Ascidian, Halocynthia roretzi J. Biol. Chem., June 1, 2001; 276(23): 19959 - 19965. [Abstract] [Full Text] [PDF]
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C.-B. Chen and R. Wallis Stoichiometry of Complexes between Mannose-binding Protein and Its Associated Serine Proteases. DEFINING FUNCTIONAL UNITS FOR COMPLEMENT ACTIVATION J. Biol. Chem., July 6, 2001; 276(28): 25894 - 25902. [Abstract] [Full Text] [PDF]
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V. Rossi, S. Cseh, I. Bally, N. M. Thielens, J. C. Jensenius, and G. J. Arlaud Substrate Specificities of Recombinant Mannan-binding Lectin-associated Serine Proteases-1 and -2 J. Biol. Chem., October 26, 2001; 276(44): 40880 - 40887. [Abstract] [Full Text] [PDF]
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