Title : Structural basis for the
sheddase function of human
meprin β 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 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