Heparan sulfate regulates ADAM12 through a molecular switch mechanism.
The disintegrin and metalloproteases (ADAMs) are emerging as therapeutic targets in human disease, but specific drug design is hampered by potential redundancy. Unlike other metzincins, ADAM prodomains remain bound to the mature enzyme to regulate activity. Here ADAM12, a protease that promotes tumor progression and chondrocyte proliferation in osteoarthritic cartilage, is shown to possess a prodomain/catalytic domain cationic molecular switch, regulated by exogenous heparan sulfate and heparin but also endogenous cell surface proteoglycans and the polyanion, calcium pentosan polysulfate. Sheddase functions of ADAM12 are regulated by the switch, as are proteolytic functions in placental tissue and sera of pregnant women. Moreover, human heparanase, an enzyme also linked to tumorigenesis, can promote ADAM12 sheddase activity at the cell surface through cleavage of the inhibitory heparan sulfate. These data present a novel concept that might allow targeting of ADAM12 and suggest that other ADAMs may have specific regulatory activity embedded in their prodomain and catalytic domain structures.
Sørensen
Hans Peter
HP
Department of Biomedicine and Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N, Denmark.
Vivès
Romain R
RR
Manetopoulos
Christina
C
Albrechtsen
Reidar
R
Lydolph
Magnus C
MC
Jacobsen
Jonas
J
Couchman
John R
JR
Wewer
Ulla M
UM
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072199:ADAM12 Protein; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D006224:Cricetinae; D004789:Enzyme Activation; D005966:Glucuronidase / Q000378:metabolism; D006025:Glycosaminoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010003:Osteoarthritis / Q000201:enzymology; D011485:Protein Binding; D013379:Substrate Specificity; D000099175:Heparanase
D051722:ADAM Proteins; D000072199:ADAM12 Protein; D005966:Glucuronidase; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D008565:Membrane Proteins; D000099175:Heparanase; C020341:glucosaminoglycans; C000606480:ADAM12 protein, human