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

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Arolas Joan L, Broder Claudia, Jefferson Tamara, Guevara Tibisay, Sterchi Erwin E, Bode Wolfram, Stöcker Walter, Becker-Pauly Christoph, Gomis-Rüth F Xavier,
Project Meprins, membrane-bound and secreted Astacinmetalloproteinases: Function in intestinal Epithelium
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Original article (peer-reviewed)

Journal Proceedings of the National Academy of Sciences of the United States of America
Volume (Issue) 109(40)
Page(s) 16131 - 6
Title of proceedings Proceedings of the National Academy of Sciences of the United States of America
DOI 10.1073/pnas.1211076109

Abstract

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.
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