Inhibition of bone morphogenetic protein 1 by native and altered forms of alpha2-macroglobulin.
The four mammalian bone morphogenetic protein 1 (BMP1)-like proteinases act to proteolytically convert procollagens to the major fibrous components of the extracellular matrix. They also activate lysyl oxidase, an enzyme necessary to the covalent cross-linking that gives collagen fibrils much of their tensile strength. Thus, these four proteinases are attractive targets for interventions designed to limit the excess formation of fibrous collagenous matrix that characterizes fibrosis. Although it has previously been reported that the serum protein alpha(2)-macroglobulin is unable to inhibit the astacin-like proteinases meprin alpha and meprin beta, we herein demonstrate alpha(2)-macroglobulin to be a potent inhibitor of the similar BMP1-like proteinases. BMP1 is shown to cleave the alpha(2)-macroglobulin "bait" region, at a single specific site, which resembles the sites at which BMP1-like proteinases cleave the C-propeptides of procollagens I-III. alpha(2)-Macroglobulin is an irreversible inhibitor that is shown to bind bone morphogenetic protein 1 in a covalent complex. It is also demonstrated that genetically modified alpha(2)-macroglobulin, in which the native bait region is replaced by sequences flanking the probiglycan BMP1 cleavage site, is enhanced approximately 24-fold in its ability to inhibit BMP1, and is capable of inhibiting the biosynthetic processing of procollagen I by cells. These findings suggest possible therapeutic interventions involving ectopic expression of modified versions of alpha(2)-macroglobulin in the treatment of fibrotic conditions.
Zhang
Yue
Y
Program in Cellular and Molecular Biology, the Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, Wisconsin 53706, USA.
Ge
Gaoxiang
G
Greenspan
Daniel S
DS
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D058578:Biglycan; D055395:Bone Morphogenetic Protein 1; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors*; D003094:Collagen / Q000737:chemistry; D016326:Extracellular Matrix Proteins / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D007930:Leucine / Q000737:chemistry; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D051379:Mice; D008969:Molecular Sequence Data; D011485:Protein Binding; D011509:Proteoglycans / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D000511:alpha-Macroglobulins / Q000737:chemistry* / Q000378:metabolism
C546884:BGN protein, human; C546885:Bgn protein, mouse; D058578:Biglycan; D019485:Bone Morphogenetic Proteins; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D011994:Recombinant Proteins; D000511:alpha-Macroglobulins; D003094:Collagen; D008666:Metalloendopeptidases; C525705:BMP1 protein, human; C525707:Bmp1 protein, mouse; D055395:Bone Morphogenetic Protein 1; D007930:Leucine