The GxxxG motif in the transmembrane domain of AbetaPP plays an essential role in the interaction of CTF beta with the gamma-secretase complex and the formation of amyloid-beta.
Gamma-secretase-mediated processing of the amyloid-beta protein precursor (AbetaPP) is a crucial step in the formation of the amyloid-beta peptide (Abeta), but little is known about how the substrate AbetaPP interacts with the gamma-secretase complex. To understand the molecular events involved in gamma-secretase-mediated AbetaPP processing and Abeta formation, in the present study we determined the role of a well conserved GxxxG motif in the transmembrane domain of AbetaPP. Our data clearly demonstrate that substitution of aspartic acid for the key glycine residues in the GxxxG motif almost completely abolished the formation of Abeta. Furthermore, our data revealed that substitution of aspartic acid for the glycine in this GxxxG motif disrupts the interaction of AbetaPP with the gamma-secretase complex. Thus, the present study revealed an essential role for the GxxxG motif in the interaction of AbetaPP with the gamma-secretase complex and the formation of Abeta.
Mao
Guozhang
G
Department of Pathobiology College of Veterinary Medicine, The University of Tennessee, Knoxville, TN 37996, USA.
Tan
Jianxin
J
Cui
Mei-Zhen
MZ
Chui
Dehua
D
Xu
Xuemin
X
D000409:Alanine / Q000235:genetics; D020816:Amino Acid Motifs / Q000235:genetics; D019943:Amino Acid Substitution / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000737:chemistry / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D005998:Glycine / Q000235:genetics; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D051379:Mice; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017434:Protein Structure, Tertiary / Q000502:physiology; D013379:Substrate Specificity / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010446:Peptide Fragments; C543304:amyloid beta-protein precursor C-terminal fragment beta, human; D053829:Amyloid Precursor Protein Secretases; D000409:Alanine; D005998:Glycine