DOI: 10.1523/jneurosci.3614-06.2006. Structure of the Catalytic Pore of γ-Secretase Probed by the Accessibility of Substituted Cysteines

Structure of the Catalytic Pore of γ-Secretase Probed by the Accessibility of Substituted Cysteines

10.1523/jneurosci.3614-06.2006

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

Abstract

Several single-span membrane proteins are cleaved within their transmembrane domains (TMDs) by intramembrane-cleaving proteases, although the structure of the active site executing intramembrane cleavage remains unknown. Here we use the substituted cysteine accessibility method to examine the structure of presenilin-1, a catalytic subunit of γ-secretase, involved in amyloid β protein generation in Alzheimer's disease and Notch signaling. We show that TMD6 and TMD7 of presenilin-1 contribute to the formation of a hydrophilic pore within the membrane. Residues at the luminal portion of TMD6 are predicted to form a subsite for substrate or inhibitor binding on the α-helix facing a hydrophilic milieu, whereas those around the GxGD catalytic motif within TMD7 are highly water accessible, suggesting formation of a hydrophilic structure within the pore. Collectively, our data suggest that the active site of γ-secretase resides in a catalytic pore filled with water within the lipid bilayer and is tapered around the catalytic aspartates.

Bibliography

Sato, C., Morohashi, Y., Tomita, T., & Iwatsubo, T. (2006). Structure of the Catalytic Pore of Î³-Secretase Probed by the Accessibility of Substituted Cysteines. The Journal of Neuroscience, 26(46), 12081â12088.

Authors 4

Chihiro Sato (first)
Yuichi Morohashi (additional)
Taisuke Tomita (additional)
Takeshi Iwatsubo (additional)

References 43 Referenced 125

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Dates

Type	When
Created	18 years, 9 months ago (Nov. 15, 2006, 9:56 p.m.)
Deposited	2 years, 4 months ago (April 13, 2023, 1:44 p.m.)
Indexed	1 year ago (Aug. 5, 2024, 5:55 p.m.)
Issued	18 years, 9 months ago (Nov. 15, 2006)
Published	18 years, 9 months ago (Nov. 15, 2006)
Published Online	18 years, 9 months ago (Nov. 15, 2006)
Published Print	18 years, 9 months ago (Nov. 15, 2006)

Funders 0

None

BibTeX

@article{Sato_2006, title={Structure of the Catalytic Pore of γ-Secretase Probed by the Accessibility of Substituted Cysteines}, volume={26}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.3614-06.2006}, DOI={10.1523/jneurosci.3614-06.2006}, number={46}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Sato, Chihiro and Morohashi, Yuichi and Tomita, Taisuke and Iwatsubo, Takeshi}, year={2006}, month=nov, pages={12081–12088} }

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