The metzincin clan encompasses several families of zinc-dependent metalloproteases with proven function both in physiology and pathology. They act either as broad spectrum protein degraders or as sheddases, operating through limited proteolysis. Among the structurally uncharacterized metzincin families are the pappalysins, of which the most thoroughly studied member is human pregnancy-associated plasma protein A (PAPP-A), a heavily glycosylated 170-kDa multidomain protein specifically cleaving insulin-like growth factor (IGF)-binding proteins (IGFBPs). Proulilysin is a 38-kDa archaeal protein that shares sequence similarity with PAPP-A but encompasses only the pro-domain and the catalytic domain. It undergoes calcium-mediated autolytic activation, and the mature protein adopts a three-dimensional structure with two subdomains separated by an active site cleft containing the catalytic zinc ion. This structure is reminiscent of human members of the adamalysin/ADAMs (a disintegrin and a metalloprotease) family of metzincins. A bound dipeptide yields information on the substrate specificity of ulilysin, which specifically hydrolyzes IGFBP-2 to -6, insulin, and extracellular matrix proteins but not IGFBP-1 or IGF-II. Accordingly, ulilysin has higher proteolytic efficiency and a broader substrate specificity than human PAPP-A. The structure of ulilysin represents a prototype for the catalytic domain of pappalysins. Insulin-like growth factors (IGF)-I and -II4 regulate human somatic growth and development. Their activity is also correlated with several diseases, including atherosclerosis, cardiovascular disease, diabetes, and cancer (1). Most circulating IGF molecules are sequestered in complexes with soluble IGF-binding proteins (IGFBP-1 to -6) (2). IGFBPs antagonize binding of IGFs to their receptors because of their much higher affinity, and they are thus carriers, mediators, and reservoirs of IGFs (3). IGFs are released from these complexes with IGFBP through proteolytic inactivation mediated by IGFBP proteases, which include serine proteinases, cysteine proteinases, and metalloproteases (MPs). Among these, human PAPP-A specifically inactivates IGFBPs (4 -6). This MP was originally identified as an antigen in human pregnancy plasma (7). It is ubiquitously expressed and plays central roles in ovarian follicular development, myogenesis, human embryo implantation, and wound healing (8). Mature PAPP-A is a glycosylated multidomain protein of 1,547 residues that specifically hydrolyzes human IGFBP-4 in an IGF-dependent manner. Only human IGFBP-5 and bovine and porcine IGFBP-2 have been identified as further substrates (6). In addition to its proteolytic domain, three Lin12-Notch repeats (LNR-1, -2, and -3), modules that regulate ligand-induced proteolytic cleavage of the Notch receptor, and five complement control protein modules (CCP1-5) have been identified (9). Human PAPP-A is the founding member of the pappalysin family of MPs, which further comprehends the paralogue PAPP-A2 (10) and has been included in the metzinc...

The only endogenous protein inhibitor known for metallocarboxypeptidases (MCPs) is latexin, a 25-kDa protein discovered in the rat brain. Latexin, alias endogenous carboxypeptidase inhibitor, inhibits human CPA4 (hCPA4), whose expression is induced in prostate cancer cells after treatment with histone deacetylase inhibitors. hCPA4 is a member of the A͞B subfamily of MCPs and displays the characteristic ␣͞␤-hydrolase fold. Human latexin consists of two topologically equivalent subdomains, reminiscent of cystatins, consisting of an ␣-helix enveloped by a curved ␤-sheet. These subdomains are packed against each other through the helices and linked by a connecting segment encompassing a third ␣-helix. The enzyme is bound at the interface of these subdomains. The complex occludes a large contact surface but makes rather few contacts, despite a nanomolar inhibition constant. This low specificity explains the flexibility of latexin in inhibiting all vertebrate A͞B MCPs tested, even across species barriers. In contrast, modeling studies reveal why the N͞E subfamily of MCPs and invertebrate A͞B MCPs are not inhibited. Major differences in the loop segments shaping the border of the funnel-like access to the protease active site impede complex formation with latexin. Several sequences ascribable to diverse tissues and organs have been identified in vertebrate genomes as being highly similar to latexin. They are proposed to constitute the latexin family of potential inhibitors. Because they are ubiquitous, latexins could represent for vertebrate A͞B MCPs the counterparts of tissue inhibitors of metalloproteases for matrix metalloproteinases.metallocarboxypeptidase ͉ metalloprotease ͉ x-ray crystal structure

Psoriatic lesions can be induced by anti-TNF drugs. Plaque psoriasis on the extremities and trunk were the most frequent presentations in our series. Topical steroid treatment is effective in most patients. Anti-TNF discontinuance may be reserved for patients with severe psoriasis or patients without response to topical therapy.