Dimerization of the transmembrane domain of amyloid precursor protein is determined by residues around the gamma-secretase cleavage sites [Cell Biology]

One of the hallmarks of Alzheimer's disease (AD) 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 (APP). While 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 (BRET) and the 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 (T43-V44-I45-V46; (TVIV)) as well as its local secondary structure as critical determinants for homodimerization. These four amino acids are also a hotspot of familial AD (FAD)-linked mutations that both decrease C99 homodimerization and γ-secretase cleavage and alter the initial cleavage site to increase the Aβ42/40 ratio.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2vM4hi0
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