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Sampling the conformational space of the catalytic subunit of human γ-secretase
Xiao‐chen Bai, Eeson Rajendra, Guanghui Yang, Yigong Shi, Sjors H. W. Scheres. eLife, 2015-12-01
Topic: Disease mechanisms in lab and animal studies
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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APA 7th
Bai, X., Rajendra, E., Yang, G., Shi, Y., & Scheres, S. H. W. (2015). Sampling the conformational space of the catalytic subunit of human γ-secretase. eLife. https://doi.org/10.7554/elife.11182
Vancouver
Bai X, Rajendra E, Yang G, Shi Y, Scheres SHW. Sampling the conformational space of the catalytic subunit of human γ-secretase. eLife. 2015. doi:10.7554/elife.11182. PMID: 26623517.
BibTeX
@article{bai2015-26623517,
author = {Bai, Xiao‐chen and Rajendra, Eeson and Yang, Guanghui and Shi, Yigong and Scheres, Sjors H. W.},
title = {{Sampling the conformational space of the catalytic subunit of human γ-secretase}},
journal = {eLife},
year = {2015},
doi = {10.7554/elife.11182},
pmid = {26623517},
url = {https://doi.org/10.7554/elife.11182}
}
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Key findings
- Our previous cryo-EM structure of γ-secretase revealed considerable disorder in its catalytic subunit presenilin.
- 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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Study details
- Evidence strengthLow
How this study scored 43/100
Published in a leading specialty journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on journal's citation record, times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 25 of the 58 points we could judge it on, which is 43 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 9 / 10 | Tier 2 — leading specialty journal (eLife) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2015 — within 20 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 26623517) |
| Free to read | 2 / 2 | Free to read |
| Points | 25 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 25 of the 58 points we could judge it on is 43 out of 100. |
| Total | 43 / 100 | — |
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