4GWN

Crystal structure of human mature meprin beta

Summary for 4GWN

• Entry DOI: 10.2210/pdb4gwn/pdb
• Related: 4GWM
• Descriptor: Meprin A subunit beta, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-3)][alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: multidomain structure, hydrolase
• Biological source: Homo sapiens (human)
• Cellular location: Cell membrane ; Single-pass type I membrane protein: Q16820
• Total number of polymer chains: 1
• Total formula weight: 67819.65

Authors

Arolas, J.L.,Broder, C.,Jefferson, T.,Guevara, T.,Sterchi, E.E.,Bode, W.,Stocker, W.,Becker-Pauly, C.,Gomis-Ruth, F.X. (deposition date: 2012-09-03, release date: 2012-09-19, Last modification date: 2024-11-13)

Primary citation

Arolas, J.L.,Broder, C.,Jefferson, T.,Guevara, T.,Sterchi, E.E.,Bode, W.,Stocker, W.,Becker-Pauly, C.,Gomis-Ruth, F.X.
Structural basis for the sheddase function of human meprin beta metalloproteinase at the plasma membrane
Proc.Natl.Acad.Sci.USA, 109:16131-16136, 2012

PubMed 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.

PubMed: 22988105
DOI: 10.1073/pnas.1211076109

Experimental method

X-RAY DIFFRACTION (3 Å)