Cellular localization of Nicastrin affects amyloid beta species production
Morais, Vanessa Leight, Susan Pijak, Donald S Lee, Virginia M. -Y Costa, Julia # ×
Elsevier on behalf of the Federation of European Biochemical Societies
FEBS Letters vol:582 issue:3 pages:427-433
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 (A beta), predominantly A beta 40, whereas intracellular targeted mutants produced intracellular A beta, with a comparatively higher amount of A beta 42. These results suggest that compartmental microenvironments play a role in gamma-secretase activity and specificity. (C) 2008 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.