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Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10.

Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, Janes PW, Rubinstein E, Nikolov DB, Skiniotis G, Kruse AC, Blacklow SC
Cell 171 1638-1648.e7 (2017)
Cited: 80 times
EuropePMC logo PMID: 29224781

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.

Reviews - 6be6 mentioned but not cited (7)

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Articles - 6be6 mentioned but not cited (11)

  1. Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10. Seegar TCM, Killingsworth LB, Saha N, Meyer PA, Patra D, Zimmerman B, Janes PW, Rubinstein E, Nikolov DB, Skiniotis G, Kruse AC, Blacklow SC. Cell 171 1638-1648.e7 (2017)
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Reviews citing this publication (29)

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  23. Neuropathogenesis of HIV-1: insights from across the spectrum of acute through long-term treated infection. Killingsworth L, Spudich S. Semin Immunopathol 44 709-724 (2022)
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  27. Heparin-binding epidermal growth factor and fibroblast growth factor 2 rescue Müller glia-derived progenitor cell formation in microglia- and macrophage-ablated chick retinas. El-Hodiri HM, Bentley JR, Reske AG, Taylor OB, Palazzo I, Campbell WA, Halloy NR, Fischer AJ. Development 150 dev202070 (2023)
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