Cellular localization of Nicastrin affects amyloid beta species production.
The gamma-secretase complex, composed by presenilin, nicastrin, APH-1 and PEN-2, is involved in intramembranous proteolysis of membrane proteins, such as amyloid precursor protein or Notch. Cleavage occurs in multiple cellular compartments. Here, nicastrin mutants containing targeting signals to the endoplasmic reticulum, trans-Golgi network, lysosomes, or plasma membrane have been shown to yield active gamma-secretase complexes with different activities and specificities: wild-type and plasma membrane nicastrin complexes yielded the highest amounts of secreted amyloid-beta peptide (Abeta), predominantly Abeta40, whereas intracellular targeted mutants produced intracellular Abeta, with a comparatively higher amount of Abeta42. These results suggest that compartmental microenvironments play a role in gamma-secretase activity and specificity.
Morais
Vanessa A
VA
Instituto de Tecnologia Química e Biológica, Apartado 127, Oeiras 2781-901, Portugal.
Leight
Susan
S
Pijak
Donald S
DS
Lee
Virginia M-Y
VM
Costa
Júlia
J
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism* / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000378:metabolism; D050505:Mutant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D014018:Tissue Distribution / Q000502:physiology
D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D050505:Mutant Proteins; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases