Structure and function of TM6SF1 reveals role in mTORC1 signaling

• 成果类型: Article
• 署名作者: Hong, Sen; Jia, Liangjie; Wang, Rong; Elghobashi-Meinhardt, Nadia; Hobbs, Helen H.; Li, Xiaochun
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2622424123
• 发表日期: 2026-09-22
• 页码: e2622424123
• 关键词: TM6SF1; cryo-em; mtorc1; lamtor1; transcription factor EB; molecular-dynamics; software news; v-atpase; association; LIPIDATION; expression; proteins; SLC38A9; PATHWAY; efflux

摘要

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-& Aring; 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.