DOI: 10.1073/pnas.032395699. The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain

The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain

10.1073/pnas.032395699

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

Abstract

Proteolytic processing of the amyloid precursor protein by β-secretase generates C99, which subsequently is cleaved by γ-secretase, yielding the amyloid β peptide (Aβ). This γ-cleavage occurs within the transmembrane domain (TMD) of C99 and is similar to the intramembrane cleavage of Notch. However, Notch and C99 differ in their site of intramembrane cleavage. The main γ-cleavage of C99 occurs in the middle of the TMD, whereas the cleavage of Notch occurs close to the C-terminal end of the TMD, making it unclear whether both are cleaved by the same protease. To investigate whether γ-cleavage always occurs in the middle of the TMD of C99 or may also occur at the end of the TMD, we generated C99-mutants with an altered length of the TMD and analyzed their γ-cleavage in COS7 cells. The C terminus of Aβ and thus the site of γ-cleavage were determined by using monoclonal antibodies and mass spectrometry. Compared with C99-wild type (wt), most mutants with an altered length of the TMD changed the cleavage site of γ-secretase, whereas control mutants with mutations outside the TMD did not. Thus, the length of the whole TMD is a major determinant for the cleavage site of γ-secretase. Moreover, the C99-mutants were not only cleaved at one site but at two sites within their TMD. One cleavage site was located around the middle of the TMD, regardless of its actual length. An additional cleavage occurred within the N-terminal half of their TMD and thus at the opposite side of the Notch cleavage site.

Bibliography

Lichtenthaler, S. F., Beher, D., Grimm, H. S., Wang, R., Shearman, M. S., Masters, C. L., & Beyreuther, K. (2002). The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain. Proceedings of the National Academy of Sciences, 99(3), 1365â1370.

Authors 7

Stefan F. Lichtenthaler (first)
Dirk Beher (additional)
Heike S. Grimm (additional)
Rong Wang (additional)
Mark S. Shearman (additional)
Colin L. Masters (additional)
Konrad Beyreuther (additional)

References 39 Referenced 58

Dates

Type	When
Created	23 years ago (July 26, 2002, 10:36 a.m.)
Deposited	3 years, 4 months ago (April 12, 2022, 9:05 a.m.)
Indexed	1 year, 2 months ago (June 1, 2024, 7:10 p.m.)
Issued	23 years, 7 months ago (Jan. 22, 2002)
Published	23 years, 7 months ago (Jan. 22, 2002)
Published Online	23 years, 7 months ago (Jan. 22, 2002)
Published Print	23 years, 6 months ago (Feb. 5, 2002)

Funders 0

None

BibTeX

@article{Lichtenthaler_2002, title={The intramembrane cleavage site of the amyloid precursor protein depends on the length of its transmembrane domain}, volume={99}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.032395699}, DOI={10.1073/pnas.032395699}, number={3}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Lichtenthaler, Stefan F. and Beher, Dirk and Grimm, Heike S. and Wang, Rong and Shearman, Mark S. and Masters, Colin L. and Beyreuther, Konrad}, year={2002}, month=jan, pages={1365–1370} }

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  "abstract": "<jats:p>Proteolytic processing of the amyloid precursor protein by \u03b2-secretase generates C99, which subsequently is cleaved by \u03b3-secretase, yielding the amyloid \u03b2 peptide (A\u03b2). This \u03b3-cleavage occurs within the transmembrane domain (TMD) of C99 and is similar to the intramembrane cleavage of Notch. However, Notch and C99 differ in their site of intramembrane cleavage. The main \u03b3-cleavage of C99 occurs in the middle of the TMD, whereas the cleavage of Notch occurs close to the C-terminal end of the TMD, making it unclear whether both are cleaved by the same protease. To investigate whether \u03b3-cleavage always occurs in the middle of the TMD of C99 or may also occur at the end of the TMD, we generated C99-mutants with an altered length of the TMD and analyzed their \u03b3-cleavage in COS7 cells. The C terminus of A\u03b2 and thus the site of \u03b3-cleavage were determined by using monoclonal antibodies and mass spectrometry. Compared with C99-wild type (wt), most mutants with an altered length of the TMD changed the cleavage site of \u03b3-secretase, whereas control mutants with mutations outside the TMD did not. Thus, the length of the whole TMD is a major determinant for the cleavage site of \u03b3-secretase. Moreover, the C99-mutants were not only cleaved at one site but at two sites within their TMD. One cleavage site was located around the middle of the TMD, regardless of its actual length. An additional cleavage occurred within the N-terminal half of their TMD and thus at the opposite side of the Notch cleavage site.</jats:p>",
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