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The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access
Somavarapu AK, Kepp KP.. Neurobiology of disease, 2016-02-04
Topic: Brain proteins, microglia and lab models
There is no molecular explanation for the many presenilin 1 (PSEN1) mutations causing Alzheimer's disease, but both gain of function relating to amyloid production and loss of isolated PSEN1 function have been implied. We report here the first detailed dynamic all-atom model of mature PSEN1 from molecular dynamics in an explicit membrane with particular account of the as yet unexplored loop dynamics. We find that mature PSEN1 contains multiple distinct conformational states whereas non-mature PSEN1 is a typical one-state protein. We confirm a previously suggested gating mechanism, and find that the 106-131 loop acts as a "hinge" for the TM2 and TM6 "doors". More importantly, we identify an unplugging mechanism of the Exon 9 loop associated only with mature PSEN1. Proper opening of both the "gate" and "plug" in the membrane produces channel-like morphologies and access to the catalytic aspartates. Dynamically, these features seem linked. The long-range sensitivity of this gate-plug system to subtle conformational changes can explain why so many PSEN1 mutants cause disease. Reduced access and imprecise substrate cleavage associated with impaired gate-plug dynamics is directly illustrated by the effect of maturation in our work and could explain the overall reduction in Aβ levels upon PSEN1 mutation and the increase in the Aβ 42/40 ratio. Yet, our PSEN1-only dynamics are particularly insightful in revealing PSEN1-only dynamics relating to e.g. its role as membrane channel. Thus, our identified gate-plug mechanism is relevant for designing PSEN1 modulating therapies for treatment of Alzheimer's disease within both the amyloid/γ-secretase hypothesis and within the PSEN1 loss of function paradigm.
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APA 7th
Somavarapu, A. K., & Kepp, K. P. (2016). The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access. Neurobiology of disease. https://doi.org/10.1016/j.nbd.2016.02.008
Vancouver
Somavarapu AK, Kepp KP. The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access. Neurobiology of disease. 2016. doi:10.1016/j.nbd.2016.02.008. PMID: 26852951.
BibTeX
@article{somavarapu2016-26852951,
author = {Somavarapu, A. K. and Kepp, K. P.},
title = {{The dynamic mechanism of presenilin-1 function: Sensitive gate dynamics and loop unplugging control protein access}},
journal = {Neurobiology of disease},
year = {2016},
doi = {10.1016/j.nbd.2016.02.008},
pmid = {26852951},
url = {https://doi.org/10.1016/j.nbd.2016.02.008}
}
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Key findings
- Reduced access and imprecise substrate cleavage associated with impaired gate-plug dynamics is directly illustrated by the effect of maturation in our work and could explain the overall reduction in Aβ levels upon PSEN1 mutation and the increase in the Aβ 42/40 ratio.
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Study details
- Evidence strengthLow
How this study scored 36/100
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 and multi-centre collaboration, so those were left out: it earned 21 of the 58 points we could judge it on, which is 36 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Neurobiology of disease) |
| 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 | 2016 — 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) |
| 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 26852951) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 21 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 21 of the 58 points we could judge it on is 36 out of 100. |
| Total | 36 / 100 | — |
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