Abstract
Presenilin 1 (PSI), 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 PS1 species found in normal mammalian brain, the role of endoproteolysis in the maturation of PS1 has been un- clear. 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) PS1, are relatively short-lived (t 1/4 1.5 h) proteins that give rise to the N- and C-terminal PS1 fragments, which are more stable (t 1/4 ~ 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 (ΔE9) 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 in 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 forms of wild- type huPS1.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 24536-24541 |
| Number of pages | 6 |
| Journal | Journal of Biological Chemistry |
| Volume | 272 |
| Issue number | 39 |
| DOIs | |
| State | Published - Sep 26 1997 |
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ASJC Scopus subject areas
- Biochemistry
Cite this
Endoproteolytic processing and stabilization of wild-type and mutant presenilin. / Ratovitski, Tamara; Slunt, Hilda H.; Thinakaran, Gopal; Price, Donald L.; Sisodia, Sangram S.; Borchelt, David R.
In: Journal of Biological Chemistry, Vol. 272, No. 39, 26.09.1997, p. 24536-24541.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Endoproteolytic processing and stabilization of wild-type and mutant presenilin
AU - Ratovitski, Tamara
AU - Slunt, Hilda H.
AU - Thinakaran, Gopal
AU - Price, Donald L.
AU - Sisodia, Sangram S.
AU - Borchelt, David R.
PY - 1997/9/26
Y1 - 1997/9/26
N2 - Presenilin 1 (PSI), 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 PS1 species found in normal mammalian brain, the role of endoproteolysis in the maturation of PS1 has been un- clear. 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) PS1, are relatively short-lived (t 1/4 1.5 h) proteins that give rise to the N- and C-terminal PS1 fragments, which are more stable (t 1/4 ~ 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 (ΔE9) 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 in 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 forms of wild- type huPS1.
AB - Presenilin 1 (PSI), 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 PS1 species found in normal mammalian brain, the role of endoproteolysis in the maturation of PS1 has been un- clear. 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) PS1, are relatively short-lived (t 1/4 1.5 h) proteins that give rise to the N- and C-terminal PS1 fragments, which are more stable (t 1/4 ~ 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 (ΔE9) 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 in 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 forms of wild- type huPS1.
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UR - http://www.scopus.com/inward/citedby.url?scp=0030854388&partnerID=8YFLogxK
U2 - 10.1074/jbc.272.39.24536
DO - 10.1074/jbc.272.39.24536
M3 - Article
C2 - 9305918
AN - SCOPUS:0030854388
VL - 272
SP - 24536
EP - 24541
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 39
ER -