APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes.
APH-1 and PEN-2 genes modulate the function of nicastrin and the presenilins in Caenorhabditis elegans. Preliminary studies in transfected mammalian cells overexpressing tagged APH-1 proteins suggest that this genetic interaction is mediated by a direct physical interaction. Using the APH-1 protein encoded on human chromosome 1 (APH-1(1)L; also known as APH-1a) as an archetype, we report here that endogenous forms of APH-1 are predominantly expressed in intracellular membrane compartments, including the endoplasmic reticulum and cis-Golgi. APH-1 proteins directly interact with immature and mature forms of the presenilins and nicastrin within high molecular weight complexes that display gamma- and epsilon-secretase activity. Indeed APH-1 proteins can bind to the nicastrin delta312-369 loss of function mutant, which does not undergo glycosylation maturation and is not trafficking beyond the endoplasmic reticulum. The levels of expression of endogenous APH-1(1)L can be suppressed by overexpression of any other members of the APH-1 family, suggesting that their abundance is coordinately regulated. Finally, although the absence of APH-1 destabilizes the presenilins, in contrast to nicastrin and PEN-2, APH-1 itself is only modestly destabilized in cells lacking functional expression of presenilin 1 or presenilin 2. Taken together, our data suggest that APH-1 proteins, and APH-1(1) in particular, may have a role in the initial assembly and maturation of presenilin.nicastrin complexes.
Gu
Yongjun
Y
Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
Chen
Fusheng
F
Sanjo
Nobuo
N
Kawarai
Toshitaka
T
Hasegawa
Hiroshi
H
Duthie
Monica
M
Li
Wenping
W
Ruan
Xueying
X
Luthra
Anchla
A
Mount
Howard T J
HT
Tandon
Anurag
A
Fraser
Paul E
PE
St George-Hyslop
Peter
P
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D002384:Catalysis; D002460:Cell Line; D002498:Centrifugation; D018076:DNA, Complementary / Q000378:metabolism; D010450:Endopeptidases; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006031:Glycosylation; D006056:Golgi Apparatus / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000378:metabolism*; D008969:Molecular Sequence Data; D010447:Peptide Hydrolases; D011233:Precipitin Tests; D053764:Presenilin-1; D053766:Presenilin-2; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D014162:Transfection; D014283:Triiodobenzoic Acids / Q000494:pharmacology
D018076:DNA, Complementary; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D014283:Triiodobenzoic Acids; C413604:nicastrin protein; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; C044834:iodixanol