[21] Snake venom metalloendopeptidases: Reprolysins

SummarySequencing of an Ixodes pacificus salivary gland cDNA library yielded 1068 sequences with an average undetermined nucleotide of 1.9% and an average length of 487 base pairs. Assembly of the expressed sequence tags yielded 557 contigs, 138 of which appear to code for secreted peptides or proteins based on translation of a putative signal peptide. Based on the BLASTX similarity of these contigs to 66 matches of Ixodes scapularis peptide sequences, only 58% sequence identity was found, indicating a rapid divergence of salivary proteins as observed previously for mosquito and triatomine bug salivary proteins. Here we report 106 mostly full-length sequences that clustered in 16 different families: Basic-tail proteins rich in lysine in the carboxy-terminal, Kunitz-containing proteins (monolaris, ixolaris and penthalaris families), proline-rich peptides, 5-kDa.-, 9.4 kDa.-, and 18.7 kDa.-proteins of unknown functions, in addition to metalloproteases (class PIII-like) similar to reprolysins. We also have found a family of disintegrins, named ixodegrins that display homology to variabilin, a GPIIb/IIIa antagonist from the tick Dermacentor variabilis. In addition, we describe peptides (here named ixostatins) that display remarkable similarities to the cysteine-rich domain of ADAMST-4 (aggrecanase). Many molecules were assigned in the lipocalin family (histaminebinding proteins); others appear to be involved in oxidant metabolism, and still others were similar to ixodid proteins such as the anticomplement ISAC. We also identified for the first time a neuropeptide-like protein (nlp-31) with GGY repeats that may have antimicrobial activity. In addition, 16 novel proteins without significant similarities to other tick proteins and 37 housekeeping proteins that may be useful for phylogenetic studies are described. Some of these proteins may be useful for studying vascular biology or the immune system, for vaccine development, or as immunoreagents to detect prior exposure to ticks. Electronic version of the manuscript can be found at http://www.ncbi.nlm.nih.gov/projects/omes/.

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“…These enzymes are organized into four classes, PI through PIV, according to size and domain composition (Bjarnason and Fox, 1995).…”

Section: Group 8: Metalloproteasementioning

confidence: 99%

The transcriptome of the salivary glands of the female western black-legged tick Ixodes pacificus (Acari: Ixodidae)

Francischetti

Pham

Mans

et al. 2005

Insect Biochemistry and Molecular Biology

147

156

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“…7); together, the ADAMs and snake venom metalloproteinases are referred to as reprolysins (7). Most ADAM members are quite similar in domain organization (2,4,7), bearing from amino to carboxyl termini, a signal peptide, a proregion, a zinc-metalloprotease catalytic domain with the typical reprolysin signature HEX 1 X 2 HX 3 X 1 GX 1 XHD (X is typically: a hydrophobic residue (superscript 1), glycine or a hydrophobic residue (superscript 2), asparagine (superscript 3)), a disintegrin domain, a cysteine-rich domain, an epidermal growth factor-like domain, and in many cases a membrane-spanning region and a cytoplasmic domain with signaling potential. A recently described murine gene encoded a secreted protein that differed substantially from the prototypic ADAM structure and was designated ADAM-TS1 2 (8).…”

mentioning

confidence: 99%

ADAM-TS5, ADAM-TS6, and ADAM-TS7, Novel Members of a New Family of Zinc Metalloproteases

Hurskainen¹,

Hirohata²,

Seldin³

et al. 1999

Journal of Biological Chemistry

194

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We report the primary structure of three novel, putative zinc metalloproteases designated ADAM-TS5, ADAM-TS6, and ADAM-TS7. All have a similar domain organization, comprising a preproregion, a reprolysintype catalytic domain, a disintegrin-like domain, a thrombospondin type-1 (TS) module, a cysteine-rich domain, a spacer domain without cysteine residues, and a COOH-terminal TS module. These genes are differentially regulated during mouse embryogenesis and in adult tissues, with Adamts5 highly expressed in the periimplantation period in embryo and trophoblast. These proteins are similar to four other cognate gene products, defining a distinct family of human reprolysin-like metalloproteases, the ADAM-TS family. The other members of the family are ADAM-TS1, an inflammation-induced gene, the procollagen I/II amino-propeptide processing enzyme (PCINP, ADAM-TS2), and proteins predicted by the KIAA0366 and KIAA0688 genes (ADAM-TS3 and ADAM-TS4). Individual ADAM-TS members differ in the number of COOH-terminal TS modules, and some have unique COOH-terminal domains. The ADAM-TS genes are dispersed in human and mouse genomes. Proteolysis of extracellular matrix (ECM)1 plays a critical role in establishing tissue architecture during development and in tissue degradation in diseases such as cancer, arthritis, Alzheimer's disease, and a variety of inflammatory conditions (1-3). The proteolytic enzymes responsible include members of diverse protease families and they may work in concert or in cascades to degrade or process molecules. Two groups of zinc metalloproteases in particular, ADAMs (a disintegrin and metalloprotease) (2-4) and MMPs (matrix metalloproteinases) (1), appear broadly relevant to extracellular proteolysis. These families include a large number of enzymes (over 20 gene products each) with demonstrated cleavage activity for matrix molecules as well as nonmatrix, bioactive molecules such as tumor necrosis factor-␣ (reviewed in Ref. 3). In other instances of extracellular proteolysis, such as cleavage of aggrecan at the Glu 373 -Ala 374 peptide bond (5) or the shedding of L-selectin from leukocytes (6), the responsible proteases have not yet been reported. Such activities may eventually be attributed to cognate proteases but they may well be due to one or more hitherto unknown enzymes. For these reasons, it is important to define the full repertoire of enzymes possessed by cells, their regulation, and their substrate preferences.ADAMs, also referred to as MDC (metalloprotease-disintegrins with cysteine-rich domains, 2) have catalytic domains with zinc-binding signatures and disintegrin domains that are very similar to the snake venom metalloproteinases (reviewed in Ref. 7); together, the ADAMs and snake venom metalloproteinases are referred to as reprolysins (7). Most ADAM members are quite similar in domain organization (2, 4, 7), bearing from amino to carboxyl termini, a signal peptide, a proregion, a zinc-metalloprotease catalytic domain with the typical reprolysin signature HEX 1 X 2 HX 3 X 1 GX 1 XHD (X i...

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“…SVMPs are members of the Reprolysin subfamily of the M12 family of metalloproteinases (3). Of the SVMPs, the PIII class is distinguished by being comprised of proproteinase, proteinase, disintegrin-like, and cysteine-rich domains (4).…”

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confidence: 99%

The Cysteine-rich Domain of Snake Venom Metalloproteinases Is a Ligand for von Willebrand Factor A Domains

Serrano

Kim

Wang

et al. 2006

Journal of Biological Chemistry

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Snake venom metalloproteinases (SVMPs) are members of the Reprolysin family of metalloproteinases to which the ADAM (a disintegrin and metalloproteinase) proteins also belong. The disintegrin-like/cysteine-rich domains of the ADAMs have been implicated in their function. In the case of the SVMPs, we hypothesized that these domains could function to target the metalloproteinases to key extracellular matrix proteins or cell surface proteins. Initially we detected interaction of collagen XIV, a fibril-associated collagen with interrupted triple helices containing von Willebrand factor A (VWA) domains, with the PIII SVMP catrocollastatin. Next we investigated whether other VWA domain-containing matrix proteins could support the binding of PIII SVMPs. Using surface plasmon resonance, the PIII SVMP jararhagin and a recombinant cysteine-rich domain from a PIII SVMP were demonstrated to bind to collagen XIV, collagen XII, and matrilins 1, 3, and 4. Jararhagin was shown to cleave these proteins predominantly at sites localized at or near the VWA domains suggesting that it is the VWA domains to which the PIII SVMPs are binding via their cysteine-rich domain. In light of the fact that these extracellular matrix proteins function to stabilize matrix, targeting the SVMPs to these proteins followed by their specific cleavage could promote the destabilization of extracellular matrix and cell-matrix interactions and in the case of capillaries could contribute to their disruption and hemorrhage. Although there is only limited structural homology shared by the cysteine-rich domains of the PIII SVMPs and the ADAMs our results suggest an analogous function for the cysteine-rich domains in certain members of the expanded ADAM family of proteins to target them to VWA domain-containing proteins.One of the hallmarks of viperid envenoming is local hemorrhage caused by the snake venom metalloproteinases (SVMPs) 2 (1, 2). SVMPs are members of the Reprolysin subfamily of the M12 family of metalloproteinases (3). Of the SVMPs, the PIII class is distinguished by being comprised of proproteinase, proteinase, disintegrin-like, and cysteine-rich domains (4). The proteinase domain of all the SVMP hemorrhagic toxins is believed to function to degrade capillary basement membranes, endothelial cell surfaces, and stromal matrix ultimately causing extravasation of capillary contents into the surround stroma (5, 6). Interestingly the PIII class of SVMPs is typically much more potent in causing hemorrhage compared with the PI and PII classes that lack the cysteine-rich domain found in the PIII class (4) suggesting a role for this domain in the pathophysiology of the PIII hemorrhagic toxins. Indeed the disintegrin-like/cysteine-rich domains of certain hemorrhagic toxins have been shown to be potent inhibitors of collagen-induced platelet aggregation as a result of interaction of the cysteine-rich domain with the ␣2␤1 integrin on platelets (7,8). Proteolytic degradation of capillary basement membrane structures and inhibition of platelet aggregation have...

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[21] Snake venom metalloendopeptidases: Reprolysins

Cited by 249 publications

References 107 publications

The transcriptome of the salivary glands of the female western black-legged tick Ixodes pacificus (Acari: Ixodidae)

The transcriptome of the salivary glands of the female western black-legged tick Ixodes pacificus (Acari: Ixodidae)

ADAM-TS5, ADAM-TS6, and ADAM-TS7, Novel Members of a New Family of Zinc Metalloproteases

The Cysteine-rich Domain of Snake Venom Metalloproteinases Is a Ligand for von Willebrand Factor A Domains

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