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Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane
Joan L Arolas1, Claudia Broder, Tamara Jefferson
1Proteolysis Laboratory, Department of Structural Biology, Molecular Biology Institute of Barcelona, Consejo Superior de Investigaciones Cientificas, Barcelona Science Park, E-08028 Barcelona, Spain.
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.
Insights
Human meprin β, a metallopeptidase, sheds proteins involved in inflammation and cleaves amyloid precursor protein (APP). Its crystal structure reveals insights into its function in ectodomain shedding and disease pathways.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Ectodomain shedding regulates cell signaling proteins.
- Meprin β (a metallopeptidase) sheds cytokines and growth factors, impacting inflammation, angiogenesis, and tumor progression.
- Meprin β also cleaves amyloid precursor protein (APP), generating amyloidogenic peptides.
Purpose of the Study:
- To determine the X-ray crystal structure of a meprin β ectoprotein fragment and its zymogen.
- To elucidate the structural basis of meprin β's function as a multidomain oligomeric transmembrane sheddase.
Main Methods:
- X-ray crystallography was used to solve the structures of meprin β ectoprotein fragment and its zymogen.
- Structural analysis of the meprin β dimer was performed.
Main Results:
- The crystal structure of the meprin β ectoprotein fragment and its zymogen were determined.
- The meprin β dimer exhibits a compact structure with a catalytic domain that rearranges upon activation.
- An exosite and a sugar-rich channel potentially involved in substrate binding were identified.
Conclusions:
- The structure provides insights into the mechanism of ectodomain shedding by meprin β.
- A proposed mechanism suggests APP shedding occurs near the plasma membrane via an "N-like" trace.
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