摘要γ-Secretase,called"the proteasome of the membrane,"is a membrane-embedded protease complex that cleaves 150+peptide substrates with central roles in biology and medicine,including amyloid precursor protein and the Notch family of cell-surface receptors.Mutations in γ-secretase and amyloid precursor protein lead to early-onset familial Alzheimer's disease.γ-Secretase has thus served as a critical drug target for treating familial Alzheimer's disease and the more common late-onset Alzheimer's disease as well.However,critical gaps remain in understanding the mechanisms of processive proteolysis of substrates,the effects of familial Alzheimer's disease mutations,and allosteric modulation of substrate cleavage by γ-secretase.In this review,we focus on recent studies of structural dynamic mechanisms of γ-secretase.Different mechanisms,including the"Fit-Stay-Trim,""Sliding-Unwinding,"and"Tilting-Unwinding,"have been proposed for substrate proteolysis of amyloid precursor protein by γ-secretase based on all-atom molecular dynamics simulations.While an incorrect registry of the Notch1 substrate was identified in the cryo-electron microscopy structure of Notch1-bound γ-secretase,molecular dynamics simulations on a resolved model of Notch1-bound γ-secretase that was reconstructed using the amyloid precursor protein-bound γ-secretase as a template successfully captured γ-secretase activation for proper cleavages of both wildtype and mutant Notch,being consistent with biochemical experimental findings.The approach could be potentially applied to decipher the processing mechanisms of various substrates by γ-secretase.In addition,controversy over the effects of familial Alzheimer's disease mutations,particularly the issue of whether they stabilize or destabilize γ-secretase-substrate complexes,is discussed.Finally,an outlook is provided for future studies of γ-secretase,including pathways of substrate binding and product release,effects of modulators on familial Alzheimer's disease mutations of the γ-secretase-substrate complexes.Comprehensive understanding of the functional mechanisms of γ-secretase will greatly facilitate the rational design of effective drug molecules for treating familial Alzheimer's disease and perhaps Alzheimer's disease in general.