Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the γ-secretase cleavage sites

Yan Yan, Ting Hai Xu, Kaleeckal G. Harikumar, Laurence J Miller, Karsten Melcher, H. Eric Xu

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

One of the hallmarks of Alzheimer’s disease is the formation of extracellular amyloid plaques that consist mainly of abnormally aggregated forms of amyloid β (Aβ) peptides. These peptides are generated by γ-secretase– catalyzed cleavage of a dimeric membrane-bound C-terminal fragment (C99) of the amyloid precursor protein. Although C99 homodimerization has been linked to Aβ production and changes in the aggregation-determining Aβ42/Aβ40 ratio, the motif through which C99 dimerizes has remained controversial. Here, we have used two independent assays to gain insight into C99 homodimerization in the context of the membrane of live cells: bioluminescence resonance energy transfer and Tango membrane protein–protein interaction assays, which were further confirmed by traditional pull-down assays. Our results indicate a four-amino acid region within the C99 transmembrane helix (43TVIV46) as well as its local secondary structure as critical determinants for homodimerization. These four amino acids are also a hot spot of familial Alzheimer’s disease–linked mutations that both decrease C99 homodimerization and γ-secretase cleavage and alter the initial cleavage site to increase the Aβ42/40 ratio.

Original languageEnglish (US)
Pages (from-to)15826-15837
Number of pages12
JournalJournal of Biological Chemistry
Volume292
Issue number38
DOIs
StatePublished - Sep 22 2017

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Amyloid Precursor Protein Secretases
Dimerization
Amyloid beta-Protein Precursor
Assays
Membranes
Amyloid
Amino Acids
Peptides
Energy Transfer
Amyloid Plaques
Bioluminescence
Alzheimer Disease
Cell Membrane
Energy transfer
Mutation
Agglomeration

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the γ-secretase cleavage sites. / Yan, Yan; Xu, Ting Hai; Harikumar, Kaleeckal G.; Miller, Laurence J; Melcher, Karsten; Xu, H. Eric.

In: Journal of Biological Chemistry, Vol. 292, No. 38, 22.09.2017, p. 15826-15837.

Research output: Contribution to journalArticle

Yan, Yan ; Xu, Ting Hai ; Harikumar, Kaleeckal G. ; Miller, Laurence J ; Melcher, Karsten ; Xu, H. Eric. / Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the γ-secretase cleavage sites. In: Journal of Biological Chemistry. 2017 ; Vol. 292, No. 38. pp. 15826-15837.
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