The DOI matches its Crossref record; 6 of the 6 references it cites were found in a registry or an index.
Sampling the conformational space of the catalytic subunit of human γ-secretase
Open accessAbstract
Human γ-secretase is an intra-membrane protease that cleaves many different substrates. Aberrant cleavage of Notch is implicated in cancer, while abnormalities in cutting amyloid precursor protein lead to Alzheimer's disease. Our previous cryo-EM structure of γ-secretase revealed considerable disorder in its catalytic subunit presenilin. Here, we describe an image classification procedure that characterizes molecular plasticity at the secondary structure level, and apply this method to identify three distinct conformations in our previous sample. In one of these conformations, an additional transmembrane helix is visible that cannot be attributed to the known components of γ-secretase. In addition, we present a γ-secretase structure in complex with the dipeptidic inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT). Our results reveal how conformational mobility in the second and sixth transmembrane helices of presenilin is greatly reduced upon binding of DAPT or the additional helix, and form the basis for a new model of how substrate enters the transmembrane domain.
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Cites
RELION: Implementation of a Bayesian approach to cryo-EM structure determination
Scheres, S. H. W. (2012) · Journal of Structural Biology · doi:10.1016/j.jsb.2012.09.006 · Cited by 5,446
Self-citationRosenthal, P. B., & Henderson, R. (2003) · Journal of Molecular Biology · doi:10.1016/j.jmb.2003.07.013 · Cited by 2,416
Aph-1, Pen-2, and Nicastrin with Presenilin Generate an Active γ-Secretase Complex
De Strooper, B. (2003) · Neuron · doi:10.1016/s0896-6273(03)00205-8 · Cited by 965
Lessons from a failed γ-secretase Alzheimer trial
De Strooper, B. (2014) · Cell · doi:10.1016/j.cell.2014.10.016 · Cited by 277
Structure of the SecY channel during initiation of protein translocation
Park, E., Ménétret, J.-F., Gumbart, J. C., Ludtke, S. J., Li, W., Whynot, A., Rapoport, T. A., & Akey, C. W. (2014) · Nature · doi:10.1038/nature12720 · Cited by 148
Wakabayashi, T., Craessaerts, K., Bammens, L., Bentahir, M., Borgions, F., Herdewijn, P., Staes, A., Timmerman, E., Vandekerckhove, J., Rubinstein, E., et al. (2009) · Nature Cell Biology · doi:10.1038/ncb1978 · Cited by 135
Cited by
cryoSPARC: algorithms for rapid unsupervised cryo-EM structure determination
Punjani, A., Rubinstein, J. L., Fleet, D. J., & Brubaker, M. A. (2017) · Nature Methods · doi:10.1038/nmeth.4169 · Cited by 11,626
Structural basis of STING binding with and phosphorylation by TBK1
Zhang, C., Shang, G., Gui, X., Zhang, X., Bai, X.-C., & Chen, Z. J. (2019) · Nature · doi:10.1038/s41586-019-1000-2 · Cited by 1,095
Self-citationStructure and mechanogating mechanism of the Piezo1 channel
Zhao, Q., Zhou, H., Chi, S., Wang, Y., Wang, J., Geng, J., Wu, K., Liu, W., Zhang, T., Dong, M.-Q., et al. (2018) · Nature · doi:10.1038/nature25743 · Cited by 628
Atomic structure of Hsp90-Cdc37-Cdk4 reveals that Hsp90 traps and stabilizes an unfolded kinase
Verba, K. A., Wang, R. Y.-R., Arakawa, A., Liu, Y., Shirouzu, M., Yokoyama, S., & Agard, D. A. (2016) · Science · doi:10.1126/science.aaf5023 · Cited by 424
Recognition of the amyloid precursor protein by human γ-secretase
Zhou, R., Yang, G., Guo, X., Zhou, Q., Lei, J., & Shi, Y. (2019) · Science · doi:10.1126/science.aaw0930 · Cited by 304
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Metadata
- Authors
- Bai, X.-C., Rajendra, E., Yang, G., Shi, Y., & Scheres, S. H.
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2015-12-01
- Volume
- 4
- ISSN
- 2050-084X (ISSN-L)
- OpenAlex
- W2120396539
- Cited by
- 552
- References
- 6
- FWCI
- 41.75
- Type
- journal article
- Language
- en
- Open access
- gold
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