Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms
Melissa D Stuchell-Brereton, Maxwell I Zimmerman, Justin J Miller, Upasana L Mallimadugula, J Jeremías Incicco, Debjit Roy, Louis G Smith, Jasmine Cubuk et al.. Proceedings of the National Academy of Sciences of the United States of America, 2023-02-07
Topic: Genetics and APOE
The ε4-allele variant of apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimer's disease, although it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. Previous studies have led to conflicting models of the C-terminal region positioning with respect to the N-terminal domain across isoforms largely because the data are potentially confounded by the presence of heterogeneous oligomers. Here, we apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically detailed model of monomeric ApoE4 and probe the effect of lipid association. Importantly, our approach overcomes previous limitations by allowing us to work at picomolar concentrations where only the monomer is present. Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids. Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble. Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein.
Key findings
- Our data reveal that ApoE4 is far more disordered and extended than previously thought and retains significant conformational heterogeneity after binding lipids.
- Comparing the proximity of the N- and C-terminal domains across the three major isoforms (ApoE4, ApoE3, and ApoE2) suggests that all maintain heterogeneous conformations in their monomeric form, with ApoE2 adopting a slightly more compact ensemble.
- Overall, these data provide a foundation for understanding how ApoE4 differs from nonpathogenic and protective variants of the protein.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 41/100
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 23 of the 56 points we could judge it on, which is 41 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences of the United States of America) |
| 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 | 3 / 5 | 2023 — within 6 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 36749730) |
| Free to read | — / 2 | Access not recorded — left out of this score |
| Points | 23 / 56 | Scored on 10 of 20 parts. We have no data for the rest, so they are left out: 23 of the 56 points we could judge it on is 41 out of 100. |
| Total | 41 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
Free copy unknown: no free-copy check has an answer for this record yet. That does not mean it is paywalled.
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. The record's author list ends in “et al.”, so not every author is named. Check the citation against the original before you use it.
APA 7th
Stuchell-Brereton, M. D., Zimmerman, M. I., Miller, J. J., Mallimadugula, U. L., Incicco, J. J., Roy, D., et al. (2023). Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proceedings of the National Academy of Sciences of the United States of America. https://doi.org/10.1073/pnas.2215371120
Vancouver
Stuchell-Brereton MD, Zimmerman MI, Miller JJ, Mallimadugula UL, Incicco JJ, Roy D, et al. Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms. Proceedings of the National Academy of Sciences of the United States of America. 2023. doi:10.1073/pnas.2215371120. PMID: 36749730.
BibTeX
@article{stuchellbrereton2023-36749730,
author = {Stuchell-Brereton, Melissa D and Zimmerman, Maxwell I and Miller, Justin J and Mallimadugula, Upasana L and Incicco, J Jeremías and Roy, Debjit and Smith, Louis G and Cubuk, Jasmine and others},
title = {{Apolipoprotein E4 has extensive conformational heterogeneity in lipid-free and lipid-bound forms}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2023},
doi = {10.1073/pnas.2215371120},
pmid = {36749730},
url = {https://doi.org/10.1073/pnas.2215371120}
}
Related studies in Genetics
Also tagged “apoe2”
266 studies in the library carry the topic tag “apoe2”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 266 tagged studies.