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

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 ? 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 ?-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin ? ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin ? 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.

SUBMITTER: Arolas JL 

PROVIDER: S-EPMC3479590 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature