A toxin homology domain in an astacin-like metalloproteinase of the jellyfish Podocoryne carnea with a dual role in digestion and development

Abstract

Metalloproteinases of the astacin family such as tolloid play major roles in animal morphogenesis. Cnidarians are thought to be evolutionary simple organisms and, therefore, a metalloproteinase from the marine hydrozoan Podocoryne carnea was analysed to evaluate the role of this conserved gene familiy at the base of animal evolution. Surprisingly, the proteinase domain of Podocornyne PMP1 is more similar to human meprin than to HMP1 from another hydrozoan, the freshwater polyp Hydra vulgaris. However, PMP1 and HMP1 both contain a small C-terminal domain with six cysteines that distinguishes them from other astacin-like molecules. Similar domains have been described only recently from sea anemone toxins specific for potassium channels. This toxin homology (Tox1) domain is clearly distinct from epidermal growth factor (EGF)-like domains or other cysteine-rich modules and terminates with the characteristic pattern CXXXCXXC with three out of six cysteines in the last eight residues of the protein. PMP1 is transiently expressed at various sites of morphogenetic activity during medusa bud development. In the adult medusa, however, expression is concentrated to the manubrium, the feeding organ, where the PMP1 gene is highly induced upon feeding. These disparate expression patterns suggest a dual role of PMP1 comparable to tolloid in development and, like astacin in the crayfish, also for food digestion. The Tox1 domain of PMP1 could serve as a toxin to keep the pray paralysed after ingestion, but as a sequence module such Tox1 domains with six cysteines are neither restricted to cnidarians nor to toxins.

Potassium Channel Modulation by a Toxin Domain in Matrix Metalloprotease 23

“…MAB-7, male abnormal protein 7 (accession number NP_508174). PMP1-Jellyfish, Podocoryne metalloproteinase 1 (58).…”

Silencing of the hydra serine protease inhibitorKazal1gene mimics the humanSPINK1pancreatic phenotype

“…Metalloproteinases are highly conserved multifunctional enzymes, involved in morphogenetic as well as digestive processes in cnidarians (Pan et al, 1998;Sarras et al, 2002). In bilaterians, protease inhibitors restrict their activity according to a tight balance that prevents cellular defects as autodigestion (Witt et al, 2000), abnormal cell migration and metastasis.…”

Structure, expression, and developmental function of early divergent forms of metalloproteinases in Hydra

“…The processed HMP-1 wou ld have a predicted molecular mass of 27×10 3 , fit ting well with the size of purified HMP-1. Matur e HMP-1 has a relatively simple structure consist ing of a well-conserved astacin domain followed by a Cys-rich domain that was also identified in P MP-1 as a toxin homology (TH) domain [21]. A zi nc-binding motif and a Met-turn, both characteri stics of astacin proteinases were also well conserv ed in HMP-1 (Fig 1A) [20].…”

“…T he domain structure of HMP-1 resembles that of other astacin family members (Fig 1A).An N-ter minal hydrophbic region of 21 residues with the c haracteristics of a putative signal sequence sugge sts that HMP-1 is a secreted proteinase. A 30-res idue prodomain was identified based on its homo logy to the same region of Podocoryne metallopro teinase-1 (PMP-1) [21]. The existence of the pro domain was further supported by the N-terminal sequence of purified HMP-1, which suggested a proteolytic cleavage of secreted HMP-1 between Phe(51) and Lys (52).…”

“…The MAM domain is also present in the extracellular segment of many cell surface proteins with diverse functions. These proteins include proteinases like meprin α [24] and β [25], receptors involved in neuronal recognition and angiogenesis such as neuropilin-1 and 2 [26], cell adhesion proteins like zonadhesin [27], [28], and receptor tyrosine phos-phatase mu-like molecules [29].The C-terminal cysrich domain of HMP-2 is homologous to the TH toxin domain in HMP-1 [16] and PMP-1 [21].…”