Related Experiment Video
Updated: Jun 10, 2025
07:49
Spontaneous Formation and Rearrangement of Artificial Lipid Nanotube Networks as a Bottom-Up Model for Endoplasmic Reticulum
Published on: January 22, 2019
7.8K
Membrane structure-responsive lipid scrambling by TMEM63B to control plasma membrane lipid distribution
Yugo Miyata1,2, Katsuya Takahashi3, Yongchan Lee3
1Department of Medical Chemistry, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Nature Structural & Molecular Biology
|October 18, 2024
Summary
Transmembrane protein 63B (TMEM63B) acts as a lipid scramblase, responding to membrane changes to control phospholipid distribution. Mutations in TMEM63B disrupt this process, impacting plasma membrane asymmetry and linked to neurodevelopmental disorders.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Phospholipids exhibit asymmetric distribution in the plasma membrane (PM), crucial for cellular function.
- Mechanisms regulating phospholipid asymmetry, particularly phosphatidylcholine and sphingomyelin in the outer leaflet, are not fully understood.
Purpose of the Study:
- To investigate the function of transmembrane protein 63B (TMEM63B) in regulating phospholipid distribution at the plasma membrane.
- To elucidate the molecular mechanisms underlying TMEM63B's lipid scrambling activity and its role in membrane homeostasis.
Main Methods:
- Utilized cryo-electron microscopy to determine the structures of TMEM63B in open and closed conformations.
- Investigated TMEM63B's function as a membrane structure-responsive lipid scramblase.
- Analyzed the impact of TMEM63B deficiency and mutations on phospholipid distribution.
Main Results:
- Identified TMEM63B as a membrane structure-responsive scramblase localized at the plasma membrane and lysosomes.
- Demonstrated that TMEM63B's scrambling activity is modulated by membrane curvature and thickness, involving palmitoylated cysteine residues.
- Showed that TMEM63B deficiency disrupts phosphatidylcholine and sphingomyelin distribution, and the V44M mutation causes constitutive activity, impairing PM phospholipid asymmetry.
Conclusions:
- TMEM63B plays a critical role in controlling plasma membrane phospholipid distribution through membrane structure-responsive lipid scrambling.
- The study reveals the molecular basis of TMEM63B's lipid translocation pathway and its biological significance, including links to neurodevelopmental disorders associated with TMEM63B mutations.
Related Concept Videos
01:28Assembly of the Lipid Bilayer in the ER
3.1K
Biological membranes are more than just a barrier separating cell cytoplasm from the outside environment. They are highly dynamic and help maintain the integrity and physiological stability of the cells as well as membrane-bound organelles. Membranes also play vital roles in cell-to-cell and intracellular communication.
A large chunk of any biological membrane is composed of phospholipids. These lipids have a heterogeneous distribution across different subcellular organelles and even between...
A large chunk of any biological membrane is composed of phospholipids. These lipids have a heterogeneous distribution across different subcellular organelles and even between...
3.1K
01:19Membrane Asymmetry Regulating Transporters
4.3K
Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
4.3K
01:26Membrane Fluidity
11.0K
Membrane fluidity is explained by the fluid mosaic model of the cell membrane, which describes the plasma membrane structure as a mosaic of components—including phospholipids, cholesterol, proteins, and carbohydrates—that gives the membrane a fluid character.
Mosaic nature of the membrane
The mosaic characteristic of the membrane helps the plasma membrane remain fluid. The integral proteins and lipids exist as separate but loosely-attached molecules in the membrane. The membrane is...
Mosaic nature of the membrane
The mosaic characteristic of the membrane helps the plasma membrane remain fluid. The integral proteins and lipids exist as separate but loosely-attached molecules in the membrane. The membrane is...
11.0K
01:35Asymmetric Lipid Bilayer
7.2K
Biological membranes show uneven distribution of different types of lipids in the inner and outer layers, resulting in transverse asymmetric membranes. The treatment of the erythrocyte membrane with the enzyme phospholipase confirmed the asymmetric nature of the lipid bilayer. The enzyme hydrolyzes lipids into fatty acids and hydrophilic groups. The phospholipase acts only on the outer layer of the membrane, while the inner layer remains intact. The phospholipase treatment resulted in 80%...
7.2K
01:15Mechanisms of Membrane-bending
2.6K
The living membranes are flexible due to their fluid mosaic nature; however, their bending into different shapes is an active process regulated by specific lipids and proteins. The membrane bending can be transient as seen in vesicles or stable for a long time as in microvilli. Cells regulate the size, location, and duration of the membrane curvature.
Membrane bending can happen due to intrinsic changes in lipid composition or extrinsic association with different proteins. The proteins involved...
Membrane bending can happen due to intrinsic changes in lipid composition or extrinsic association with different proteins. The proteins involved...
2.6K
01:19Fluid Mosaic Model
11.5K
Scientists identified the plasma membrane in the 1890s and its principal chemical components (lipids and proteins) by 1915. The model for plasma membrane structure, proposed in 1935 by Hugh Davson and James Danielli, was the first model to be widely accepted in the scientific community. The model was based on the plasma membrane's "railroad track" appearance in early electron micrographs. Davson and Danielli theorized that the plasma membrane's structure resembled a sandwich...
11.5K