Molecular analysis of ulilysin, the structural prototype of a new family of metzincin metalloproteases.
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.
Tallant
Cynthia
C
Departament de Biologia Estructural, Institut de Biologia Molecular de Barcelona, Consejo Superior de Investigaciones Científicas, c/Jordi Girona 18-26, E-08034 Barcelona, Spain.
García-Castellanos
Raquel
R
Seco
Jordi
J
Baumann
Ulrich
U
Gomis-Rüth
F Xavier
FX
D000595:Amino Acid Sequence; D002118:Calcium / Q000378:metabolism; D003461:Crystallography; D006801:Humans; D045726:Metalloproteases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D017020:Methanosarcina / Q000201:enzymology* / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family / Q000235:genetics*; D011266:Pregnancy-Associated Plasma Protein-A / Q000235:genetics; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D045726:Metalloproteases; C512490:ulilysin, Methanosarcina acetivorans; D011266:Pregnancy-Associated Plasma Protein-A; D002118:Calcium