Histidine 131 in presenilin 1 is the pH-sensitive residue that causes the increase in Aβ42 level in acidic pH
Histidine 131 in presenilin 1 is the pH-sensitive residue that causes the increase in Aβ42 level in acidic pH
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DOI：
10.1093/jb/mvz110
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发表时间：
2020-05-01
影响因子：
2.7
通讯作者：
Tomita, Taisuke
中科院分区：
文献类型：
--
作者：
Cai, Tetsuo;Hatano, Aki;Tomita, Taisuke
Alzheimer disease (AD) is the most common neurodegenerative disease worldwide. The pathological hallmark of AD is the presence of senile plaques in the brain, which are accumulations of amyloid-beta peptide (A beta) ending at the 42nd residue (i.e. A beta 42), which is produced through multistep cleavage by gamma-secretase. Thus, methods to regulate gamma-secretase activity to attenuate the production of A beta 42 are in urgent demand towards the development of treatments for AD. We and others have demonstrated that gamma-secretase activity is affected by its localization and ambient environment. In particular, an increase in A beta 42 production is correlated with the intracellular transport of gamma-secretase and endosomal maturation-dependent luminal acidification. In this study, we focused on the mechanism by which gamma-secretase affects A beta 42 production together with alterations in pH. Histidine is known to function as a pH sensor in many proteins, to regulate their activities through the protonation state of the imidazole side chain. Among the histidines facing the luminal side of presenilin (PS) 1, which is the catalytic subunit of gamma-secretase, point mutations at H131 had no effect on the A beta 42 production ratio in an acidic environment. We also observed an increase in A beta 42 ratio when histidine was introduced into N137 of PS2, which is the corresponding residue of H131 in PS1. These results indicated that H131 serves as the pH sensor in PS1, which contains gamma-secretase, to regulate A beta 42 production depending on the luminal pH. Our findings provide new insights into therapeutic strategies for AD targeting endosomes or the intracellular transport of gamma-secretase.
