Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane
- University of Chicago, United States
- Harvard T H Chan School of Public Health, United States
- Colorado School of Mines, United States
- Howard Hughes Medical Institute, Harvard T H Chan School of Public Health, United States
Abstract
Lipid droplets (LDs) are organelles formed in the endoplasmic reticulum (ER) to store triacylglycerol (TG) and sterol esters. The ER protein seipin is key for LD biogenesis. Seipin forms a cage-like structure, with each seipin monomer containing a conserved hydrophobic helix (HH) and two transmembrane (TM) segments. How the different parts of seipin function in TG nucleation and LD budding is poorly understood. Here, we utilized molecular dynamics simulations of human seipin, along with cell-based experiments, to study seipin's functions in protein-lipid interactions, lipid diffusion, and LD maturation. An all-atom (AA) simulation indicates that seipin TM segment residues and hydrophobic helices residues located in the phospholipid (PL) tail region of the bilayer attract TG. Simulating larger, growing LDs with coarse-grained (CG) models, we find that the seipin TM segments form a constricted neck structure to facilitate conversion of a flat oil lens into a budding LD. Using cell experiments and simulations, we also show that conserved, positively charged residues at the end of seipin's TM segments affect LD maturation. We propose a model in which seipin TM segments critically function in TG nucleation and LD growth.
Data availability
Numerical data represented as a graph in this manuscript are available at github.com/ksy141/seipin.
Article and author information
Author details
Robert V Farese Jnr
Funding
National Institutes of Health
- Robert V Farese Jnr
- Tobias C Walther
- Gregory A Voth
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Kim et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane
eLife 11:e75808.
https://doi.org/10.7554/eLife.75808
