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Publication

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

Cell | 2017

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 ID: 29224781 RIS Download

Research resources used in this publication

Additional research tools detected in this publication

GraphPad Prism (RRID:SCR_002798)

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Associated grants

Agency: NIGMS NIH HHS, United States
Id: P41 GM103403
Agency: NHLBI NIH HHS, United States
Id: T32 HL007627
Agency: NCI NIH HHS, United States
Id: R01 CA092433
Agency: NINDS NIH HHS, United States
Id: R01 NS038486
Agency: NCI NIH HHS, United States
Id: R35 CA220340
Agency: NCI NIH HHS, United States
Id: P01 CA119070

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GraphPad Prism (tool)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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