Binding of longer A beta to transmembrane domain 1 of presenilin 1 impacts on A beta 42 generation

作者：Ohki Yu; Shimada Naoaki; Tominaga Aya; Osawa Satoko; Higo Takuya; Yokoshima Satoshi; Fukuyama Tohru; Tomita Taisuke^*; Iwatsubo Takeshi

来源：Molecular Neurodegeneration, 2014, 9(1): 7.

DOI：10.1186/1750-1326-9-7

• Presenilin
• Secretases
• Alzheimer disease
• Intramembrane proteolysis
• gamma-Secretase modulator

Background: Amyloid-beta peptide ending at 42nd residue (A beta 42) is believed as a pathogenic peptide for Alzheimer disease. Although gamma-secretase is a responsible protease to generate A beta through a processive cleavage, the proteolytic mechanism of gamma-secretase at molecular level is poorly understood.
Results: We found that the transmembrane domain (TMD) 1 of presenilin (PS) 1, a catalytic subunit for the gamma-secretase, as a key modulatory domain for A beta 42 production. A beta 42-lowering and -raising gamma-secretase modulators (GSMs) directly targeted TMD1 of PS1 and affected its structure. A point mutation in TMD1 caused an aberrant secretion of longer A beta species including A beta 45 that are the precursor of A beta 42. We further found that the helical surface of TMD1 is involved in the binding of A beta 45/48 and that the binding was altered by GSMs as well as TMD1 mutation.
Conclusions: Binding between PS1 TMD1 and longer A beta is critical for A beta 42 production.

• 出版日期2014-1-13