Structure and function of TM6SF1 reveals role in mTORC1 signaling
What this study shows
Cryo-EM structure of TM6SF1 identifies it as a lysosomal cholesterol-binding protein that directly engages LAMTOR1 (Ragulator) to regulate mTORC1 signaling in a cholesterol-dependent manner.
Abstract
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The transmembrane 6 superfamily (TM6SF) comprises two members: TM6SF1, a ubiquitously expressed lysosomal membrane protein of unknown function, and TM6SF2, an endoplasmic reticulum protein required for bulk lipidation of Apolipoprotein B-containing lipoproteins. Here, we used cryo-electron microscopy (cryo-EM) to determine the structure of human TM6SF1 at 2.9-Å resolution. TM6SF1 forms a polytopic homodimer, with each protomer comprising 10 transmembrane helices (TMs). TMs 1-6 form a pocket that accommodates a cholesterol molecule.
Read the full abstract on PubMed →At a glance
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| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Cryo-EM structure; HEK293 cells) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Cryo-EM structure; HEK293 cells |
| Journal | Proceedings of the National Academy of Sciences |
| Year | 2026 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1073/pnas.2622424123 · PMID 42735304 |
Where this study fits
How this study connects to the pathway map, open questions, people and other studies in the Atlas.
People in the Atlas
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First-authored the cryo-EM structure identifying TM6SF1 as a lysosomal cholesterol-binding protein involved in regulating mTORC1 signalling
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Solves cryo-EM structures of cholesterol-sensing membrane proteins, including the new mTORC1 regulator TM6SF1
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Built FPTT, fluorescent 'ticker tapes' that record several signalling pathways in living cells over days, and used its mTOR version to follow mTOR activity oscillating through the cell cycle
More: 3 other authors
No profile yet: Jia L, Elghobashi-Meinhardt N, Hobbs HH
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Topics
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | TM6SF1 loss-of-function; cholesterol depletion |
| Target | TM6SF1 / LAMTOR1 / mTORC1 |
| Model | Human (HEK293 cells); cryo-EM structural study |
| Effect | Loss of TM6SF1 reduces mTORC1 signaling (S6K1/4E-BP1 phosphorylation) and activates TFEB, in a cholesterol-dependent manner |
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