First structure of a snake venom metalloproteinase: a prototype for matrix metalloproteinases/collagenases.

Abstract

Adamalysin II, a 24 kDa zinc endopeptidase from the snake venom of Crotalus adamanteus, is a member of a large family of metalloproteinases isolated as small proteinases or proteolytic domains of mosaic haemorrhagic proteins from various snake venoms. Homologous domains have recently been detected in multimodular mammalian reproductive tract proteins. The 2.0 A crystal structure of adamalysin II reveals an ellipsoidal molecule with a shallow active‐site cleft separating a relatively irregularly folded subdomain from the calcium‐binding main molecular body composed of a five‐stranded beta‐sheet and four alpha‐helices. The folding of the peptide fragment containing the zinc‐binding motif HExxHxxGxxH bears only a distant resemblance to thermolysin, but is identical to that found in astacin, with the three histidines and a water molecule (linked to the glutamic acid) likewise constituting the zinc ligand; adamalysin II lacks a fifth (tyrosine) zinc ligand, however, leaving its zinc ion tetrahedrally co‐ordinated. Furthermore, adamalysin II and astacin share an identical active‐site basement formed by a common Metturn. Due to their virtually identical active‐site environment and similar folding topology, the snake venom metalloproteinases (hitherto called adamalysins) and the astacins (and presumably also the matrix metalloproteinases/mammalian collagenases and the Serratia proteinase‐like large bacterial proteinases) might be grouped into a common superfamily with distinct differences from the thermolysin family.

Structure, function and latency regulation of a bacterial enterotoxin potentially derived from a mammalian adamalysin/ADAM xenolog

“…The adamalysin/ADAM family is named after the first family member to be structurally characterized, adamalysin II from Crotalus adamanteus snake venom, and mammalian reproductive-tract proteins (31,32). The family has 40 members in humans (http://degradome.uniovi.es/met.html#M10) and has only been found in metazoans and some fungi, which include two opportunistic human pathogens, Pneumocystis carinii and Aspergillus fumigatus; and fission yeast, Schizosaccharomyces pombe (7,(33)(34)(35).…”

Structural implications for the role of the N terminus in the ‘superactivation’ of collagenases

“…3. Truncated C,-representations of Astacin [29-301 (top), the catalytic domain of human PMNL-collagenase (middle), and Adamalysin II [27] (bottom) showing the structure of the N terminus and the main structure elements creating its environment @l, /l3,84, g5, the elements containing the 'catalytic' zinc signature, the C-terminal helix olC, and the 'catalytic' zinc ions with their liganding histidines). The N-terminal structures (Astacin: completely buried; PMNL-CL: packed but not buried; Adamalysin II: freely exposed) are related to their role in the enzymatic active species (see section 4 for details).…”

“…Fig. 3 shows the main secondary structure elements together with the N-terminal segements for PMNL-CL, astacin [29-301 and adamalysin II [27], the latter serving as examples for two other important subfamilies of the 'metzinkins' [28]. It is interesting to compare the N-terminal structures and relate them to the role of the N terminus for activation of the latent proenzyme.…”

A Novel Mechanism of Latency in Matrix Metalloproteinases

“…3, A and B). This peptide encompasses the conserved motif involved in cysteine-switch or Velcro latency characteristic of animal and plant MMPs (48 -50), 100 …”