Abstract
BackgroundThe metzincins are a large gene superfamily of proteases characterized by the presence of a zinc protease domain, and include the ADAM, ADAMTS, BMP1/TLL, meprin and MMP genes. Metzincins are involved in the proteolysis of a wide variety of proteins, including those of the extracellular matrix. The metzincin gene superfamily comprises eighty proteins in the human genome and ninety-three in the mouse. When and how the level of complexity apparent in the vertebrate metzincin gene superfamily arose has not been determined in detail. Here we present a comprehensive analysis of vertebrate metzincins using genes from both Ciona intestinalis and Danio rerio to provide new insights into the complex evolution of this gene superfamily.ResultsWe have identified 19 metzincin genes in the ciona genome and 83 in the zebrafish genome. Phylogenetic analyses reveal that the expansion of the metzincin gene superfamily in vertebrates has occurred predominantly by the simple duplication of pre-existing genes rather than by the appearance and subsequent expansion of new metzincin subtypes (the only example of which is the meprin gene family). Despite the number of zebrafish metzincin genes being relatively similar to that of tetrapods (e.g. man and mouse), the pattern of gene retention and loss within these lineages is markedly different. In addition, we have studied the evolution of the related TIMP gene family and identify a single ciona and four zebrafish TIMP genes.ConclusionThe complexity seen in the vertebrate metzincin gene families was mainly acquired during vertebrate evolution. The metzincin gene repertoire in protostomes and invertebrate deuterostomes has remained relatively stable. The expanded metzincin gene repertoire of extant tetrapods, such as man, has resulted largely from duplication events associated with early vertebrate evolution, prior to the sarcopterygian-actinopterygian split. The teleost repertoire of metzincin genes in part parallels that of tetrapods but has been significantly modified, perhaps as a consequence of a teleost-specific duplication event.
Highlights
The metzincins are a large gene superfamily of proteases characterized by the presence of a zinc protease domain, and include the ADAM, ADAMTS, BMP1/TLL, meprin and Matrix metalloproteases (MMPs) genes
Identification of metzincin genes in the ciona and zebrafish genomes A total of nineteen genes encoding metzincins were identified in the ciona genome (Table 1 & Additional File 1 & 2) comprising four ADAM, seven MMP together with the previously reported seven ADAMTS and single BMP1/tolloid gene [38,39]
These consisted of twenty-two ADAM, twenty-seven ADAMTS, four BMP1/tolloid, four meprin and twenty-six MMP orthologues (Table 2)
Summary
The metzincins are a large gene superfamily of proteases characterized by the presence of a zinc protease domain, and include the ADAM, ADAMTS, BMP1/TLL, meprin and MMP genes. Metzincins are involved in the proteolysis of a wide variety of proteins, including those of the extracellular matrix. The metzincin proteases, mainly involved in proteolysis of extracellular matrix proteins, are a gene superfamily characterized by a protease domain with a HEXXHXXGXXH zinc-binding motif at the active site [2]. Active ADAMs are membrane-bound enzymes that act as molecular switches by cleaving and releasing proteins from the cell surface through a process known as ectodomain shedding [3]. ADAM proteolysis acts upon a wide variety of growth factors, cytokines and receptors and is implicated in various cell behaviours such as angiogenesis, fertilization and neurogenesis [3]. The recent finding that ADAM22 acts as a receptor for LGI1 in regulating synaptic transmission across the neuronal membrane [8], suggest that ADAM proteins can exhibit functions separate to that of proteolysis
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