Amyloidogenic Processing but Not Amyloid Precursor Protein (APP) Intracellular C-terminal Domain Production Requires a Precisely Oriented APP Dimer Assembled by Transmembrane GXXXG Motifs

摘要: The beta-amyloid peptide (Abeta) is the major constituent of amyloid core senile plaques found in brain patients with Alzheimer disease. Abeta produced by sequential cleavage precursor protein (APP) beta- and gamma-secretases. Cleavage APP gamma-secretase also generates intracellular C-terminal domain (AICD) peptide, which might be involved regulation gene transcription. contains three Gly-XXX-Gly (GXXXG) motifs its juxtamembrane transmembrane (TM) regions. Such are known to promote dimerization via close apposition TM sequences. We demonstrate that pairwise replacement glycines leucines or isoleucines, but not alanines, a GXXXG motif led drastic reduction Abeta40 Abeta42 secretion. beta-Cleavage mutant was inhibited, secretion resulted from inhibition gamma-cleavage. It anticipated decreased gamma-cleavage would result dimerization. Surprisingly, mutations actually enhanced fragments, possibly different alpha-helical interface. Increased did affect AICD production.