Structure and function of TM6SF1 reveals role in mTORC1 signaling

Hong S, Li X et al. · 2026 · Proceedings of the National Academy of Sciences · Atlas ID HON2026

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

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	2026-09-23
Source	DOI 10.1073/pnas.2622424123 · PMID 42735304

Extracted findings

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

Cite this paper

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Hong, S., et al. (2026). Structure and function of TM6SF1 reveals role in mTORC1 signaling. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.2622424123

@article{HON2026,
  author       = {Hong, S. and Li, X. and others},
  title        = {{Structure and function of TM6SF1 reveals role in mTORC1 signaling}},
  journal      = {Proceedings of the National Academy of Sciences},
  year         = {2026},
  doi          = {10.1073/pnas.2622424123},
  note         = {PMID: 42735304},
}

Cite this Atlas record

The record is the Atlas's own work — the evidence label, the extracted findings and the links. It is cited as part of the dataset, not as the paper.

Barton, O. (2026). Oliver's mTOR Atlas (record HON2026) [Data set]. https://mtor-atlas.org/study/HON2026/ · Dataset DOI 10.5281/zenodo.22059963

@misc{atlas_HON2026,
  author       = {Barton, Oliver},
  title        = {{Oliver's mTOR Atlas}, record HON2026},
  howpublished = {Data set},
  year         = {2026},
  url          = {https://mtor-atlas.org/study/HON2026/},
  doi          = {10.5281/zenodo.22059963}
}