2024-03-28T16:49:32Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/880022021-12-28T15:47:24Zcom_10261_41com_10261_1col_10261_294
2013-12-02T12:15:46Z
urn:hdl:10261/88002
Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane
Arolas, Joan L.
Guevara, Tibisay
Bode, Wolfram
Stöcker, Walter
Gomis-Rüth, F. Xavier
Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an >N-like> chain trace.
2013-12-02T12:15:46Z
2013-12-02T12:15:46Z
2012
2013-12-02T12:15:51Z
artículo
Proceedings of the National Academy of Sciences 109(40): 16131-16136 (2012)
http://hdl.handle.net/10261/88002
10.1073/pnas.1211076109
22988105
eng
http://dx.doi.org/10.1073/pnas.1211076109
info:eu-repo/grantAgreement/EC/FP7/223101
info:eu-repo/grantAgreement/EC/FP7/261460
info:eu-repo/grantAgreement/EC/FP7/290246
openAccess
National Academy of Sciences (U.S.)