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Título

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

Autor Arolas, Joan L.; Guevara, Tibisay ; Bode, Wolfram; Stöcker, Walter; Gomis-Rüth, F. Xavier
Fecha de publicación 2012
EditorNational Academy of Sciences (U.S.)
Citación Proceedings of the National Academy of Sciences 109(40): 16131-16136 (2012)
ResumenEctodomain 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.
Versión del editorhttp://dx.doi.org/10.1073/pnas.1211076109
URI http://hdl.handle.net/10261/88002
DOI10.1073/pnas.1211076109
Identificadoresdoi: 10.1073/pnas.1211076109
e-issn: 1091-6490
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