TM6SF2 is a cholesterol-bound homomultimeric ER membrane protein that binds ApoB and is required for bulk lipidation of VLDL
- 1Howard Hughes Medical Institute/ University of Texas Southwestern Medical Center
Abstract
A missense variant in TM6SF2 (transmembrane 6 superfamily member 2, TM6SF2E167K) is a major risk factor for steatotic liver disease1, while protecting against coronary artery disease2. TM6SF2 is a polytopic resident protein of the smooth endoplasmic reticulum (ER) and ER-Golgi intermediate compartment that promotes lipidation of hepatic ApoB-containing lipoproteins before secretion into the circulation. Here, we used cryo-electron microscopy (cryo-EM) to determine the structures of TM6SF2 and TM6SF2E167K. TM6SF2 comprises 10 transmembrane helices that bind a single cholesterol molecule within a transmembrane cavity. The protein assembles into homodimers and homotetramers that interact with ApoB. Structural and biochemical analyses show that the E167K substitution reduces cholesterol binding and ApoB interaction without disrupting overall protein structure. Expression of wild-type, but not mutant, TM6SF2 restores hepatic triglyceride secretion in TM6SF2-deficient hepatocytes. Together, these findings establish the structural framework for the bulk lipidation step in hepatic lipoprotein biogenesis, the principal pathway for hepatic triglyceride and cholesterol export into the circulation.
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BibTeX
@misc{hong2026tm6sf2,
title = {{TM6SF2 is a cholesterol-bound homomultimeric ER membrane protein that binds ApoB and is required for bulk lipidation of VLDL}},
author = {S. Hong and J. Wang and M. A. Mitsche and J. C. Cohen and X. Li and H. H. Hobbs},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.17.745233},
url = {https://www.biorxiv.org/content/10.64898/2026.08.17.745233v2},
note = {CC BY},
}
RIS
TY - UNPB
TI - TM6SF2 is a cholesterol-bound homomultimeric ER membrane protein that binds ApoB and is required for bulk lipidation of VLDL
AU - S. Hong
AU - J. Wang
AU - M. A. Mitsche
AU - J. C. Cohen
AU - X. Li
AU - H. H. Hobbs
PY - 2026
DA - 2026/08/17
PB - bioRxiv
DO - 10.64898/2026.08.17.745233
UR - https://www.biorxiv.org/content/10.64898/2026.08.17.745233v2
AB - A missense variant in TM6SF2 (transmembrane 6 superfamily member 2, TM6SF2E167K) is a major risk factor for steatotic liver disease1, while protecting against coronary artery disease2. TM6SF2 is a polytopic resident protein of the smooth endoplasmic reticulum (ER) and ER-Golgi intermediate compartment that promotes lipidation of hepatic ApoB-containing lipoproteins before secretion into the circulation. Here, we used cryo-electron microscopy (cryo-EM) to determine the structures of TM6SF2 and TM6SF2E167K. TM6SF2 comprises 10 transmembrane helices that bind a single cholesterol molecule within a transmembrane cavity. The protein assembles into homodimers and homotetramers that interact with ApoB. Structural and biochemical analyses show that the E167K substitution reduces cholesterol binding and ApoB interaction without disrupting overall protein structure. Expression of wild-type, but not mutant, TM6SF2 restores hepatic triglyceride secretion in TM6SF2-deficient hepatocytes. Together, these findings establish the structural framework for the bulk lipidation step in hepatic lipoprotein biogenesis, the principal pathway for hepatic triglyceride and cholesterol export into the circulation.
ER -