Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane
Publisher DOI
PubMed ID
22988105
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.
Date Issued
2012
Publication Type
Article
Language(s)
en
Author(s)
Arolas, Joan L | |
Broder, Claudia | |
Jefferson, Tamara | |
Guevara, Tibisay | |
Bode, Wolfram | |
Stöcker, Walter | |
Becker-Pauly, Christoph | |
Gomis-Rüth, F Xavier |
Additional Credits
Journal
Proceedings of the National Academy of Sciences of the United States of America - PNAS
Publisher
National Academy of Sciences NAS
ISSN
0027-8424
Access(Rights)
metadata.only