Endoproteolytic processing and stabilization of wild-type and mutant presenilin

Tamara Ratovitski, Hilda H. Slunt, Gopal Thinakaran, Donald L. Price, Sangram S. Sisodia, David R. Borchelt

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)24536-24541
Number of pages6
JournalJournal of Biological Chemistry
Volume272
Issue number39
DOIs
StatePublished - Sep 26 1997

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Presenilins
Flavin-Adenine Dinucleotide
Alzheimer Disease
Stabilization
Presenilin-1
Terminator Codon
Pedigree
Processing
Neuroblastoma
Half-Life
Exons
Brain
Membrane Proteins
Amino Acids
Peptides
Molecules
Proteins

ASJC Scopus subject areas

  • Biochemistry

Cite this

Ratovitski, T., Slunt, H. H., Thinakaran, G., Price, D. L., Sisodia, S. S., & Borchelt, D. R. (1997). Endoproteolytic processing and stabilization of wild-type and mutant presenilin. Journal of Biological Chemistry, 272(39), 24536-24541. https://doi.org/10.1074/jbc.272.39.24536

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 journalArticle

Ratovitski, T, Slunt, HH, Thinakaran, G, Price, DL, Sisodia, SS & Borchelt, DR 1997, 'Endoproteolytic processing and stabilization of wild-type and mutant presenilin', Journal of Biological Chemistry, vol. 272, no. 39, pp. 24536-24541. https://doi.org/10.1074/jbc.272.39.24536
Ratovitski, Tamara ; Slunt, Hilda H. ; Thinakaran, Gopal ; Price, Donald L. ; Sisodia, Sangram S. ; Borchelt, David R. / Endoproteolytic processing and stabilization of wild-type and mutant presenilin. In: Journal of Biological Chemistry. 1997 ; Vol. 272, No. 39. pp. 24536-24541.
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