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Titolo:
The first proline of PALP motif at the C terminus of presenilins is obligatory for stabilization, complex formation, and gamma-secretase activities of presenilins
Autore:
Tomita, T; Watabiki, T; Takikawa, R; Morohashi, Y; Takasugi, N; Kopan, R; De Strooper, B; Iwatsubo, T;
Indirizzi:
Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Bunkyo Ku, Tokyo 1130033, Japan Univ Tokyo Tokyo Japan 1130033 Neurosci, Bunkyo Ku, Tokyo 1130033, Japan Washington Univ, Div Dermatol, St Louis, MO 63110 USA Washington Univ St Louis MO USA 63110 iv Dermatol, St Louis, MO 63110 USA Washington Univ, Dept Mol Biol & Pharmacol, St Louis, MO 63110 USA Washington Univ St Louis MO USA 63110 & Pharmacol, St Louis, MO 63110 USA Katholieke Univ Leuven, Neuronal Cell Biol Lab, B-3000 Louvain, Belgium Katholieke Univ Leuven Louvain Belgium B-3000 b, B-3000 Louvain, Belgium Flanders Interuniv Inst Biotechnol, B-3000 Louvain, Belgium Flanders Interuniv Inst Biotechnol Louvain Belgium B-3000 uvain, Belgium
Titolo Testata:
JOURNAL OF BIOLOGICAL CHEMISTRY
fascicolo: 35, volume: 276, anno: 2001,
pagine: 33273 - 33281
SICI:
0021-9258(20010831)276:35<33273:TFPOPM>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
AMYLOID-BETA-PROTEIN; DISEASE-ASSOCIATED PRESENILIN-1; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; INTRACELLULAR DOMAIN; PROTEOLYTIC RELEASE; NOTCH; ENDOPROTEOLYSIS; CLEAVAGE; MUTATION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
53
Recensione:
Indirizzi per estratti:
Indirizzo: Iwatsubo, T Univ Tokyo, Grad Sch Pharmaceut Sci, Dept Neuropathol & Neurosci, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1130033, Japan Univ Tokyo 7-3-1 Hongo Tokyo Japan 1130033 kyo 1130033, Japan
Citazione:
T. Tomita et al., "The first proline of PALP motif at the C terminus of presenilins is obligatory for stabilization, complex formation, and gamma-secretase activities of presenilins", J BIOL CHEM, 276(35), 2001, pp. 33273-33281

Abstract

Mutations in presenilin (PS) genes cause early-onset familial Alzheimer's disease by increasing production of the amyloidogenic form of amyloid beta peptides ending at residue 42 (A beta 42). PS is an evolutionarily conserved multipass transmembrane protein, and all known PS proteins contain a proline-alanine-leucine-proline (PALP) motif starting at proline (P) 414 (aminoacid numbering based on human PS2) at the C terminus. Furthermore, missense mutations that replace the first proline of PALP with leucine (P414L) lead to a loss-of-function of PS in Drosophila melanogaster and Caenorhabditiselegans. To elucidate the roles of the PALP motif in PS structure and function, we analyzed neuro2a as well as PS1/2 null fibroblast cell lines transfected with human PS harboring mutations at the PALP motif. P414L mutation in PS2 (and its equivalent in PS1) abrogated stabilization, high molecular weight complex formation, and entry to Golgi/trans-Golgi network of PS proteins, resulting in failure of A beta 42 overproduction on familial Alzheimer's disease mutant basis as well as of site-3 cleavage of Notch. These datasuggest that the first proline of the PALP motif plays a crucial role in the stabilization and formation of the high molecular weight complex of PS, the latter being the active form with intramembrane proteolytic activities.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/04/20 alle ore 00:07:40