Science1 publisher2 min readPublished
One leucine in TMEM63B's tail keeps its lipid scramblase switched off
Researchers at the Institute of Science Tokyo found that mutating one residue, Leu776, in TMEM63B's tail leaves the scramblase active without any membrane cue. The tail normally works as a brake, and earlier studies had linked disease-associated TMEM63B mutations to neurodegeneration.
The Scientist · Science desk
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What happened
- TMEM63B was already known to switch on when the cell membrane changes thickness or curvature, which left open how it stays quiet while the membrane is at rest.
- Deleting the neighboring LQD stretch at residues 776 to 778 was enough on its own to make the protein scramble lipids constitutively.
- In the open-state structure the AQVLQD motif rests against two intracellular helices, with Leu776 among hydrophobic residues that appear to lock the tail against the protein's core.
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Why it matters
- capability Pinning the off-switch to Leu776 and the LQD motif gives anyone studying disease-linked TMEM63B variants a specific residue to mutate and a readout to watch.
- constraint The scrambling was measured in engineered proteins in cultured cells, so the study locates the brake without showing that a patient's neurodegeneration runs through it.
- precedent The brake model predicts that a mutation breaking the same tail-to-domain contact would leave TMEM63B scrambling constitutively, a prediction now testable one variant at a time.
The design turned on an antibody. YN9303-24 was already known to push TMEM63B, a mechanosensitive lipid scramblase, into its open, active shape, so the researchers reasoned that its binding site would mark the region that controls the transition [1][9]. Working through chimeric proteins, progressively shortened tails and single-residue deletions, they traced the binding site to a three-residue stretch, the AQV motif at positions 773 to 775, inside the intracellular C-terminal tail [10][11]. That tail carries an autoinhibitory element that keeps the scramblase quiet at rest [2].
The control element sat next door. Deleting the neighboring LQD at residues 776 to 778 left TMEM63B scrambling lipids with no membrane stimulus at all, and narrowing the deletions singled out one residue, leucine 776 [12][13]. Swapping Leu776 for alanine drove phosphatidylserine, normally held on the cytoplasmic face, out onto the cell surface, while the same substitution at Gln777 or Asp778 did nothing [14][15]. A second readout, faster uptake of a fluorescent phosphatidylcholine, agreed that the mutant scrambled more [16].
Structure offered an explanation. In the open-state structure the AQVLQD stretch lies against two intracellular helices, IL2H2 and IL2H3, part of a beam-like domain on the inner face of the membrane [18]. Leu776 sits among several hydrophobic residues there, and the authors take this contact between the tail and that domain to be what stabilizes the protein's inactive state [19].
The study was led by graduate student Megumi Nishimura, lecturer Yugo Miyata and professor Katsumori Segawa at the Institute of Science Tokyo, working with Norimichi Nomura at Kyoto University and Tomohiro Nishizawa at Yokohama City University [7][8]. It was published in the Journal of Biological Chemistry [4]. "The C-terminal tail functions like a molecular brake, keeping TMEM63B inactive under resting conditions until changes in the membrane allow it to become activated," Segawa said [17].
The tie to neurodegeneration predates this paper. Earlier genetic studies had linked disease-associated TMEM63B mutations, and the authors present the resting-state brake as a way to understand how that dysregulation might work [20]. They say the finding may sharpen understanding of how TMEM63B dysregulation contributes to neurodegenerative disease [5].
What to watch
- Whether disease-associated TMEM63B mutations map onto the AQVLQD region or the IL2H2 and IL2H3 contact that Leu776 makes.
- A structure of the inactive state to confirm the hydrophobic contact inferred from the open-state model.
- Whether a broken brake produces constitutive scrambling in neurons or animal models rather than only in cell assays.