Amyloidogenic processing but not amyloid precursor protein (APP) intracellular C-terminal domain production requires a precisely oriented APP dimer assembled by transmembrane GXXXG motifs.
The beta-amyloid peptide (Abeta) is the major constituent of the amyloid core of senile plaques found in the brain of patients with Alzheimer disease. Abeta is produced by the sequential cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. Cleavage of APP by gamma-secretase also generates the APP intracellular C-terminal domain (AICD) peptide, which might be involved in regulation of gene transcription. APP contains three Gly-XXX-Gly (GXXXG) motifs in its juxtamembrane and transmembrane (TM) regions. Such motifs are known to promote dimerization via close apposition of TM sequences. We demonstrate that pairwise replacement of glycines by leucines or isoleucines, but not alanines, in a GXXXG motif led to a drastic reduction of Abeta40 and Abeta42 secretion. beta-Cleavage of mutant APP was not inhibited, and reduction of Abeta secretion resulted from inhibition of gamma-cleavage. It was anticipated that decreased gamma-cleavage of mutant APP would result from inhibition of its dimerization. Surprisingly, mutations of the GXXXG motif actually enhanced dimerization of the APP C-terminal fragments, possibly via a different TM alpha-helical interface. Increased dimerization of the TM APP C-terminal domain did not affect AICD production.
Kienlen-Campard
Pascal
P
Center for Neurosciences, Experimental Pharmacology Unit, Université Catholique de Louvain, B-1200 Brussels, Belgium.
Tasiaux
Bernadette
B
Van Hees
Joanne
J
Li
Mingli
M
Huysseune
Sandra
S
Sato
Takeshi
T
Fei
Jeffrey Z
JZ
Aimoto
Saburo
S
Courtoy
Pierre J
PJ
Smith
Steven O
SO
Constantinescu
Stefan N
SN
Octave
Jean-Noël
JN
D020816:Amino Acid Motifs / Q000502:physiology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D006801:Humans; D009154:Mutation; D017434:Protein Structure, Tertiary / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases