Rer1p competes with APH-1 for binding to nicastrin and regulates gamma-secretase complex assembly in the early secretory pathway.
The gamma-secretase complex, consisting of presenilin, nicastrin, presenilin enhancer-2 (PEN-2), and anterior pharynx defective-1 (APH-1) cleaves type I integral membrane proteins like amyloid precursor protein and Notch in a process of regulated intramembrane proteolysis. The regulatory mechanisms governing the multistep assembly of this "proteasome of the membrane" are unknown. We characterize a new interaction partner of nicastrin, the retrieval receptor Rer1p. Rer1p binds preferentially immature nicastrin via polar residues within its transmembrane domain that are also critical for interaction with APH-1. Absence of APH-1 substantially increased binding of nicastrin to Rer1p, demonstrating the competitive nature of these interactions. Moreover, Rer1p expression levels control the formation of gamma-secretase subcomplexes and, concomitantly, total cellular gamma-secretase activity. We identify Rer1p as a novel limiting factor that negatively regulates gamma-secretase complex assembly by competing with APH-1 during active recycling between the endoplasmic reticulum (ER) and Golgi. We conclude that total cellular gamma-secretase activity is restrained by a secondary ER control system that provides a potential therapeutic value.
Spasic
Dragana
D
Laboratory for Membrane Trafficking, Center for Human Genetics, Katholieke Universiteit Leuven/Vlaams Instituut voor Biotechnologie, Gasthuisberg, Leuven, B-3000 Leuven, Belgium.
Raemaekers
Tim
T
Dillen
Katleen
K
Declerck
Ilse
I
Baert
Veerle
V
Serneels
Lutgarde
L
Füllekrug
Joachim
J
Annaert
Wim
W
D033942:Adaptor Proteins, Vesicular Transport; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive; D015536:Down-Regulation; D010450:Endopeptidases; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008562:Membrane Glycoproteins / Q000032:analysis / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment
D033942:Adaptor Proteins, Vesicular Transport; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C109546:RER1 protein, human; C413604:nicastrin protein; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases