Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

Tom C. M. Seegar, Lauren B. Killingsworth, Nayanendu Saha, Peter A. Meyer, Dhabaleswar Patra, Brandon Zimmerman, Peter W. Janes, Eric Rubinstein, Dimitar B. Nikolov, Georgios Skiniotis, Andrew C. Kruse, Stephen C. Blacklow

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44 Citations (Scopus)

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. The X-ray structure of the ADAM10 ectodomain, together with biochemical and cell-based studies, reveals mechanistic insights into its enzymatic function in Notch signaling and in processing of the Alzheimer's precursor protein APP.

Original languageEnglish
Pages (from-to)1638-1648
Number of pages11
JournalCell
Volume171
Issue number7
DOIs
Publication statusPublished - 14 Dec 2017

Keywords

  • ADAM10
  • amyloid precursor protein
  • Notch signaling
  • X-ray crystallography

Cite this

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. (2017). Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10. Cell, 171(7), 1638-1648. https://doi.org/10.1016/j.cell.2017.11.014