2. Academic Validation
  3. Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

  • Cell. 2017 Dec 14;171(7):1638-1648.e7. doi: 10.1016/j.cell.2017.11.014.
Tom C M Seegar 1,  Lauren B Killingsworth 1,  Nayanendu Saha 2,  Peter A Meyer 3,  Dhabaleswar Patra 4,  Brandon Zimmerman 1,  Peter W Janes 5,  Eric Rubinstein 6,  Dimitar B Nikolov 2,  Georgios Skiniotis 7,  Andrew C Kruse 1,  Stephen C Blacklow 8
Affiliations

Affiliations

  • 1 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 SBGrid Initiative, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
  • 5 Department of Biochemistry and Molecular Biology, Monash University, VIC 3800, Australia.
  • 6 Inserm and Université Paris-Sud, Institut André Lwoff, Villejuif, France.
  • 7 Department of Molecular and Cellular Physiology, and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • 8 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: [email protected].
PMID: 29224781 DOI: 10.1016/j.cell.2017.11.014
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.

Keywords

ADAM10; Notch signaling; X-ray crystallography; amyloid precursor protein.

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