Journal
CELL
Volume 171, Issue 7, Pages 1638-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2017.11.014
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Funding
- NIH [5 R01 CA092433, 1 R35 CA220340, 5 T32 HL007627, R01 NS038486]
- National Institute of General Medical Sciences from NIH [P41 GM103403]
- DOE Office of Science [DE-AC02-06CH11357]
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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 a-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.
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