Endoproteolytic processing and stabilization of wild-type and mutant presenilin

被引:190
作者
Ratovitski, T
Slunt, HH
Thinakaran, G
Price, DL
Sisodia, SS
Borchelt, DR
机构
[1] JOHNS HOPKINS UNIV,SCH MED,DEPT PATHOL,BALTIMORE,MD 21205
[2] JOHNS HOPKINS UNIV,SCH MED,DIV NEUROPATHOL,BALTIMORE,MD 21205
[3] JOHNS HOPKINS UNIV,SCH MED,DEPT NEUROSCI,BALTIMORE,MD 21205
[4] JOHNS HOPKINS UNIV,SCH MED,DEPT NEUROL,BALTIMORE,MD 21205
关键词
D O I
10.1074/jbc.272.39.24536
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
Presenilin 1 (PS1), mutated in pedigrees of early-onset familial Alzheimer's disease, is a polytopic integral membrane protein that is endoproteolytically cleaved into 27-kDa N-terminal and 17-kDa C-terminal fragments, Although these fragments are the principal PSI species found in normal mammalian brain, the role of endoproteolysis in the maturation of PS1 has been unclear. The present study, which uses stably transfected mouse neuroblastoma N2a cells, demonstrates that full-length polypeptides, derived from either wild-type or A246E FAD-mutant human (hu) PSII, are relatively short-lived (t(1/2), 1.5 h) proteins that give rise to the N- and C-terminal PS1 fragments, which are more stable (t(1/2) similar to 24 h), N-terminal fragments, generated artificially by engineering a stop codon at amino acid 306 (PS1-306) of wild-type huPS1, were short-lived, whereas an FAD-linked variant that lacked exon 9 (Delta E9) and was not endoproteolytically cleaved exhibited a long half-life. These observations suggest that endoproteolytic cleavage and stability are not linked, leading us to propose a model ill which wild-type full-length huPS1 molecules are first stabilized then subsequently endoproteolytically cleaved to generate the N- and C-terminal fragments, These fragments appear to represent the mature and functional Terms of wild-type huPS1.
引用
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页码:24536 / 24541
页数:6
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