title: APH-1 interacts with mature and immature forms of presenilins and nicastrin and may play a role in maturation of presenilin.nicastrin complexes.
abstract: 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.
authors.affiliation: Centre for Research in Neurodegenerative Diseases, Department of Medicine, University of Toronto, Toronto, Ontario M5S 3H2, Canada.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gu
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sanjo
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Monica
authors.initials: M
authors.lastname: Duthie
authors.forename: Wenping
authors.initials: W
authors.lastname: Li
authors.forename: Xueying
authors.initials: X
authors.lastname: Ruan
authors.forename: Anchla
authors.initials: A
authors.lastname: Luthra
authors.forename: Howard T J
authors.initials: HT
authors.lastname: Mount
authors.forename: Anurag
authors.initials: A
authors.lastname: Tandon
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
mesh_terms: 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
chemical_list: 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