This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility: TMEM63B, a mechanosensitive lipid scramblase, has an autoinhibitory domain in its C-terminal tail that helps keep it inactive under resting conditions, researchers from the Institute of Science Tokyo report. Changes to this regulatory region, particularly the Leu776 residue, reverse the inhibitory action and cause continuous lipid scrambling, disrupting normal phospholipid asymmetry.
The findings, published in the Journal of Biological Chemistry, offer insight into TMEM63B regulation and may improve understanding of how its dysregulation contributes to neurodegenerative disease. The plasma membrane is a thin, flexible barrier that surrounds and protects cells. It maintains a carefully controlled distribution of lipids between its inner and outer layers.
This asymmetrical distribution is important for normal cellular function, but under certain conditions, lipid scramblases rapidly disrupt it by moving phospholipids between the two sides of the membrane. Cells therefore need to regulate these proteins' activity. One such protein is TMEM63B, a mechanosensitive lipid scramblase that responds to changes in the physical properties of the cell membrane.
Previous studies have shown that TMEM63B becomes active when properties such as membrane thickness or curvature change. But an important question remains: How does TMEM63B stay inactive when the membrane is at rest? To address this question, a research team led by graduate student Megumi Nishimura (at the time of the study), lecturer Yugo Miyata and professor Katsumori Segawa identified a molecular mechanism in TMEM63B.
All three are from the Department of Medical Chemistry, Medical Research Laboratory, Institute of Integrated Research, Institute of Science Tokyo (Science Tokyo), Japan. They collaborated with associate professor Norimichi Nomura from Kyoto University, Japan, and professor Tomohiro Nishizawa from Yokohama City University, Japan. The study shows that the C-terminal tail of TMEM63B plays a key role.
It has an autoinhibitory region that keeps the scramblase inactive under resting conditions. The researchers began by investigating YN9303-24, an antibody previously shown to promote the open conformation of TMEM63B. To pinpoint where the antibody binds (epitope), they used chimeric proteins (that combine regions from different proteins), progressively shortened versions of the C-terminal tail (truncations) and targeted deletions of specific amino acids.
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