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