6BE6

ADAM10 Extracellular Domain

Summary for 6BE6

• Entry DOI: 10.2210/pdb6be6/pdb
• Related: 6BDZ
• Descriptor: Disintegrin and metalloproteinase domain-containing protein 10, alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: adam10, membrane protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 4
• Total formula weight: 203797.87

Authors

Seegar, T.C.M. (deposition date: 2017-10-24, release date: 2017-12-27, Last modification date: 2024-12-25)

Primary citation

Seegar, T.C.M.,Killingsworth, L.B.,Saha, N.,Meyer, P.A.,Patra, D.,Zimmerman, B.,Janes, P.W.,Rubinstein, E.,Nikolov, D.B.,Skiniotis, G.,Kruse, A.C.,Blacklow, S.C.
Structural Basis for Regulated Proteolysis by the alpha-Secretase ADAM10.
Cell, 171:1638-1648.e7, 2017

PubMed Abstract: Cleavage of membrane-anchored proteins by ADAM (a disintegrin and metalloproteinase) endopeptidases plays a key role in a wide variety of biological signal transduction and protein turnover processes. Among ADAM family members, ADAM10 stands out as particularly important because it is both responsible for regulated proteolysis of Notch receptors and catalyzes the non-amyloidogenic α-secretase cleavage of the Alzheimer's precursor protein (APP). We present here the X-ray crystal structure of the ADAM10 ectodomain, which, together with biochemical and cellular studies, reveals how access to the enzyme active site is regulated. The enzyme adopts an unanticipated architecture in which the C-terminal cysteine-rich domain partially occludes the enzyme active site, preventing unfettered substrate access. Binding of a modulatory antibody to the cysteine-rich domain liberates the catalytic domain from autoinhibition, enhancing enzymatic activity toward a peptide substrate. Together, these studies reveal a mechanism for regulation of ADAM activity and offer a roadmap for its modulation.

PubMed: 29224781
DOI: 10.1016/j.cell.2017.11.014

Experimental method

X-RAY DIFFRACTION (2.8 Å)