Contribution of the γ-secretase subunits to the formation of catalytic pore of presenilin 1 protein.
γ-Secretase is an intramembrane-cleaving protease related to the etiology of Alzheimer disease. γ-Secretase is a membrane protein complex composed of presenilin (PS) and three indispensable subunits: nicastrin, Aph-1, and Pen-2. PS functions as a protease subunit forming a hydrophilic catalytic pore structure within the lipid bilayer. However, it remains unclear how other subunits are involved in the pore formation. Here, we show that the hydrophilic pore adopted with an open conformation has already been formed by PS within the immature γ-secretase complex. The binding of the subunits induces the close proximity between transmembrane domains facing the catalytic pore. We propose a model in which the γ-secretase subunits restrict the arrangement of the transmembrane domains of PS during the formation of the functional structure of the catalytic pore.
Department of Neuropathology and Neuroscience, Graduate School of Pharmaceutical Sciences, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Koji
K
Takeo
Naoto
N
Watanabe
Taisuke
T
Tomita
Takeshi
T
Iwatsubo
D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D010450:Endopeptidases; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010447:Peptide Hydrolases / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021122:Protein Subunits; D018411:Spodoptera
D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C469349:PSENEN protein, human; D053764:Presenilin-1; D021122:Protein Subunits; C413604:nicastrin protein; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases