GENERATION OF AN ANGIOSTATIN-LIKE FRAGMENT FROM PLASMINOGEN BY STROMELYSIN-1 (MMP-3)

Matrix metalloproteinase-3 (MMP-3 or stromelysin-1) specifically hydro lyzes the Glu(59)-Asn(60), Pro(447)-Val(448), and Pro(545)-Ser(545) pe ptide bonds in plasminogen, yielding a 55 kDa NH2-terminal angiostatin -like domain (comprising kringles 1-4), a 14 kDa domain comprising kri ngle 5, and a 30 kDa domain comprising the serine proteinase domain. T he conversion is completely abolished in the presence of the MMP inhib itors EDTA or 1,10-phenanthroline. Biospecific interaction analysis in dicates that binding of proMMP-3 and MMP-3 to plasminogen occurs with comparable affinity (K-A of 4.7 x 10(6) and 4.1 x 10(6) M-1, respectiv ely) and is mediated via the miniplasminogen moiety (kringle 5 plus th e proteinase domain) and via the catalytic domain of MMP-3. Thus, prot eolytic cleavage of plasminogen by MMP-3 generates angiostatin-like fr agments.