The First Proline of PALP Motif at the C Terminus of Presenilins is Obligatory for Stabilization, Complex Formation, and γ-Secretase Activities of Presenilins

Taisuke Tomita, Tomonari Watabiki, Rie Takikawa, Yuichi Morohashi, Nobumasa Takasugi, Raphael Kopan, Bart De Strooper, Takeshi Iwatsubo

Research output: Contribution to journalArticle

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Abstract

Mutations in presenilin (PS) genes cause early-onset familial Alzheimer's disease by increasing production of the amyloidogenic form of amyloid β peptides ending at residue 42 (Aβ42). 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 (amino acid 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 Caenorhabditis elegans. 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 Aβ42 overproduction on familial Alzheimer's disease mutant basis as well as of site-3 cleavage of Notch. These data suggest 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.

Original languageEnglish
Pages (from-to)33273-33281
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number35
DOIs
Publication statusPublished - Aug 31 2001
Externally publishedYes

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Presenilins
Amyloid Precursor Protein Secretases
Proline
Leucine
Alanine
Stabilization
Alzheimer Disease
Mutation
Molecular Weight
Molecular weight
trans-Golgi Network
Null Lymphocytes
Proteins
Caenorhabditis elegans
Missense Mutation
Fibroblasts
Drosophila melanogaster
Amyloid

ASJC Scopus subject areas

  • Biochemistry

Cite this

The First Proline of PALP Motif at the C Terminus of Presenilins is Obligatory for Stabilization, Complex Formation, and γ-Secretase Activities of Presenilins. / Tomita, Taisuke; Watabiki, Tomonari; Takikawa, Rie; Morohashi, Yuichi; Takasugi, Nobumasa; Kopan, Raphael; De Strooper, Bart; Iwatsubo, Takeshi.

In: Journal of Biological Chemistry, Vol. 276, No. 35, 31.08.2001, p. 33273-33281.

Research output: Contribution to journalArticle

Tomita, Taisuke ; Watabiki, Tomonari ; Takikawa, Rie ; Morohashi, Yuichi ; Takasugi, Nobumasa ; Kopan, Raphael ; De Strooper, Bart ; Iwatsubo, Takeshi. / The First Proline of PALP Motif at the C Terminus of Presenilins is Obligatory for Stabilization, Complex Formation, and γ-Secretase Activities of Presenilins. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 35. pp. 33273-33281.
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abstract = "Mutations in presenilin (PS) genes cause early-onset familial Alzheimer's disease by increasing production of the amyloidogenic form of amyloid β peptides ending at residue 42 (Aβ42). 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 (amino acid 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 Caenorhabditis elegans. 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 Aβ42 overproduction on familial Alzheimer's disease mutant basis as well as of site-3 cleavage of Notch. These data suggest 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.",
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