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Cryo-temperature effects on membrane protein structure and dynamics
Rukmankesh Mehra, Budheswar Dehury, Kasper P Kepp. Physical chemistry chemical physics : PCCP, 2020-03-11
Topic: Disease mechanisms in lab and animal studies
Innovations in cryogenic electron microscopy (Cryo-EM) have led to high-quality structures of important proteins such as the ribosome and γ-secretase, the membrane protease that produces Aβ involved in Alzheimer's disease. However, freezing may change protein structure and dynamics relative to the physiologically relevant "hot" state. To explore this, we studied substrate-bound γ-secretase (6IYC) by molecular dynamics as a hot, cold, and quickly cooled state in both membrane and water systems. We show that the experimental structure resembles the simulated cooled state, structurally between the hot and cold states and membrane and water systems, but with cold dynamics. We observe "cryo-contraction" in the membrane from 303 to 85 K, reducing radius of gyration (Rg) by 1% from 4.01 to 3.97 nm (6IYC = 3.95 nm). The hot state features an unwound C83-substrate with 10-14 α-helix residues (6IYC: 11) in equilibrium with an intact state with 16 helix residues not previously reported. The β-sheet is weakened with temperature. Multiple hot conformations probably control the Aβ42/Aβ40 ratio. We thus propose that MD simulation protocols of hot, cold, and cooled states as applied here can correct cryo-EM coordinates. However, important frozen-out fast modes require specific supplementary hot simulations or experiments.
Key findings
- The hot state features an unwound C83-substrate with 10-14 α-helix residues (6IYC: 11) in equilibrium with an intact state with 16 helix residues not previously reported.
- The β-sheet is weakened with temperature.
- Multiple hot conformations probably control the Aβ42/Aβ40 ratio.
- We thus propose that MD simulation protocols of hot, cold, and cooled states as applied here can correct cryo-EM coordinates.
- However, important frozen-out fast modes require specific supplementary hot simulations or experiments.
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Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / 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, multi-centre collaboration and free to read, so those were left out: it earned 22 of the 56 points we could judge it on, which is 39 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Physical chemistry chemical physics : PCCP) |
| 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 | 2 / 5 | 2020 — within 10 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) |
| Randomised / blinded | 0 / 2 | No randomisation 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 |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 31971183) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 22 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 22 of the 56 points we could judge it on is 39 out of 100. |
| Total | 39 / 100 | — |
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
APA 7th
Mehra, R., Dehury, B., & Kepp, K. P. (2020). Cryo-temperature effects on membrane protein structure and dynamics. Physical chemistry chemical physics : PCCP. https://doi.org/10.1039/c9cp06723j
Vancouver
Mehra R, Dehury B, Kepp KP. Cryo-temperature effects on membrane protein structure and dynamics. Physical chemistry chemical physics : PCCP. 2020. doi:10.1039/c9cp06723j. PMID: 31971183.
BibTeX
@article{mehra2020-31971183,
author = {Mehra, Rukmankesh and Dehury, Budheswar and Kepp, Kasper P},
title = {{Cryo-temperature effects on membrane protein structure and dynamics}},
journal = {Physical chemistry chemical physics : PCCP},
year = {2020},
doi = {10.1039/c9cp06723j},
pmid = {31971183},
url = {https://doi.org/10.1039/c9cp06723j}
}
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