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Title: Structural Basis for Regulated Proteolysis by the α-Secretase ADAM10

Journal Article · · Cell
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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. Here, 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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Inst. of General Medical Sciences; National Inst. of Health
Grant/Contract Number:
AC02-06CH11357; 5 R01 CA092433; 1 R35 CA220340; R01 NS038486; P41 GM103403
OSTI ID:
1485750
Alternate ID(s):
OSTI ID: 1430341
Journal Information:
Cell, Journal Name: Cell Vol. 171 Journal Issue: 7; ISSN 0092-8674
Publisher:
ElsevierCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 98 works
Citation information provided by
Web of Science

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
ADAM10
X-ray crystallography
amyloid precursor protein
Notch signaling