Spatial segregation of γ-secretase and substrates in distinct membrane domains

被引:188
作者
Vetrivel, KS [1 ]
Cheng, HP [1 ]
Kim, SH [1 ]
Chen, Y [1 ]
Barnes, NY [1 ]
Parent, AT [1 ]
Sisodia, SS [1 ]
Thinakaran, G [1 ]
机构
[1] Univ Chicago, Dept Neurobiol Pharmacol & Physiol, Chicago, IL 60637 USA
关键词
D O I
10.1074/jbc.M503570200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
gamma- Secretase facilitates the regulated intramembrane proteolysis of select type I membrane proteins that play diverse physiological roles in multiple cell types and tissue. In this study, we used biochemical approaches to examine the distribution of amyloid precursor protein ( APP) and several additional gamma- secretase substrates in membrane microdomains. We report that APP C- terminal fragments ( CTFs) and gamma- secretase reside in Lubrol WX detergent- insoluble membranes ( DIM) of cultured cells and adult mouse brain. APP CTFs that accumulate in cells lacking gamma- secretase activity preferentially associate with DIM. Cholesterol depletion and magnetic immunoisolation studies indicate recruitment of APP CTFs into cholesterol- and sphingolipid- rich lipid rafts, and co- residence of APP CTFs, PS1, and syntaxin 6 in DIM patches derived from the trans- Golgi network. Photoaffinity cross- linking studies provided evidence for the preponderance of active gamma- secretase in lipid rafts of cultured cells and adult brain. Remarkably, unlike the case of APP, CTFs derived from Notch1, Jagged2, deleted in colorectal cancer ( DCC), and N- cadherin remain largely detergent- soluble, indicative of their spatial segregation in non- raft domains. In embryonic brain, the majority of PS1 and nicastrin is present in Lubrol WXsoluble membranes, wherein the CTFs derived from APP, Notch1, DCC, and N- cadherin also reside. We suggest that gamma- secretase residence in non- raft membranes facilitates proteolysis of diverse substrates during embryonic development but that the translocation of gamma- secretase to lipid rafts in adults ensures processing of certain substrates, including APP CTFs, while limiting processing of other potential substrates.
引用
收藏
页码:25892 / 25900
页数:9
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