Functional reconstitution of gamma-secretase through coordinated expression of presenilin, nicastrin, Aph-1, and Pen-2.
The gamma-secretase complex has emerged as an unusual membrane-bound aspartyl protease with the ability to cleave certain substrate proteins at peptide bonds believed to be buried within the hydrophobic environment of the lipid bilayer. This cleavage is responsible for a key biochemical step in signaling from several different cell-surface receptors, and it is also crucial in generating the neurotoxic amyloid peptides that are central to the pathogenesis of Alzheimer's disease. Active gamma-secretase is a multimeric protein complex consisting of at least four different proteins, presenilin, nicastrin, Aph-1, and Pen-2, with presenilin serving as the catalytically active core of the aspartyl protease. Presenilin itself undergoes endoproteolytic maturation, a process that is tightly regulated during the assembly and maturation of gamma-secretase, and that depends on the three cofactors nicastrin, Aph-1, and Pen-2. Recent studies have demonstrated that presenilin and its three cofactors are likely to be the major proteins needed for functional reconstitution of active gamma-secretase and have begun to elucidate the specific functions of the cofactors in the ordered assembly of gamma-secretase.
Periz
Goran
G
Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, Maryland 21701, USA.
Fortini
Mark E
ME
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D046911:Macromolecular Substances; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000502:physiology; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases; D053764:Presenilin-1
D046911:Macromolecular Substances; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C469349:PSENEN protein, human; D053764:Presenilin-1; C413604:nicastrin protein; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human