title: TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity.
abstract: The presenilin proteins (PS1 and PS2) and their interacting partners nicastrin, aph-1 (refs 4, 5) and pen-2 (ref. 5) form a series of high-molecular-mass, membrane-bound protein complexes that are necessary for gamma-secretase and epsilon-secretase cleavage of selected type 1 transmembrane proteins, including the amyloid precursor protein, Notch and cadherins. Modest cleavage activity can be generated by reconstituting these four proteins in yeast and Spodoptera frugiperda (sf9) cells. However, a critical but unanswered question about the biology of the presenilin complexes is how their activity is modulated in terms of substrate specificity and/or relative activities at the gamma and epsilon sites. A corollary to this question is whether additional proteins in the presenilin complexes might subsume these putative regulatory functions. The hypothesis that additional proteins might exist in the presenilin complexes is supported by the fact that enzymatically active complexes have a mass that is much greater than predicted for a 1:1:1:1 stoichiometric complex (at least 650 kDa observed, compared with about 220 kDa predicted). To address these questions we undertook a search for presenilin-interacting proteins that differentially affected gamma- and epsilon-site cleavage events. Here we report that TMP21, a member of the p24 cargo protein family, is a component of presenilin complexes and differentially regulates gamma-secretase cleavage without affecting epsilon-secretase activity.
authors.affiliation: Department of Medicine, and Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Ontario, Canada M5S 3H2.
authors.forename: Fusheng
authors.initials: F
authors.lastname: Chen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hasegawa
authors.forename: Gerold
authors.initials: G
authors.lastname: Schmitt-Ulms
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Kawarai
authors.forename: Christopher
authors.initials: C
authors.lastname: Bohm
authors.forename: Taiichi
authors.initials: T
authors.lastname: Katayama
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Gu
authors.forename: Nobuo
authors.initials: N
authors.lastname: Sanjo
authors.forename: Michael
authors.initials: M
authors.lastname: Glista
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Rogaeva
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Wakutani
authors.forename: Raphaëlle
authors.initials: R
authors.lastname: Pardossi-Piquard
authors.forename: Xueying
authors.initials: X
authors.lastname: Ruan
authors.forename: Anurag
authors.initials: A
authors.lastname: Tandon
authors.forename: Frédéric
authors.initials: F
authors.lastname: Checler
authors.forename: Philippe
authors.initials: P
authors.lastname: Marambaud
authors.forename: Kirk
authors.initials: K
authors.lastname: Hansen
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Peter
authors.initials: P
authors.lastname: St George-Hyslop
authors.forename: Paul
authors.initials: P
authors.lastname: Fraser
mesh_terms: D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D010450:Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000737:chemistry* / Q000378:metabolism*; D029543:Nucleocytoplasmic Transport Proteins; D053764:Presenilin-1; D053766:Presenilin-2; D011485:Protein Binding; D013379:Substrate Specificity
chemical_list: D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D029543:Nucleocytoplasmic Transport Proteins; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; C484395:TMED10 protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse