10UP

Structure of human TM6SF1

Summary for 10UP

• Entry DOI: 10.2210/pdb10up/pdb
• EMDB information: 75471
• Descriptor: Transmembrane 6 superfamily member 1, CHOLESTEROL (2 entities in total)
• Functional Keywords: cholesterol, mtorc1 activity, lipid binding protein
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 84112.96

Authors

Hong, S.,Li, X. (deposition date: 2026-02-09, release date: 2026-09-09, Last modification date: 2026-09-23)

Primary citation

Hong, S.,Jia, L.,Wang, R.,Elghobashi-Meinhardt, N.,Hobbs, H.H.,Li, X.
Structure and function of TM6SF1 reveals role in mTORC1 signaling.
Proc.Natl.Acad.Sci.USA, 123:e2622424123-e2622424123, 2026

PubMed Abstract: 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. Cell-based assays revealed that loss of TM6SF1 perturbs mTORC1 signaling, resulting in reduced phosphorylation of S6 kinase 1 and 4E-BP1 and constitutive activation of transcription factor EB (TFEB), and that cholesterol is required for these effects. Biochemical analyses support the model that TM6SF1 directly engages LAMTOR1, a component of Ragulator complex, in a cholesterol-dependent manner. Together, these findings identify TM6SF1 as a lysosomal cholesterol binding protein involved in regulating mTORC1 signaling.

PubMed: 42735304
DOI: 10.1073/pnas.2622424123

Experimental method

ELECTRON MICROSCOPY (2.86 Å)