Weill Cornell Captures TMEM16F Scramblase at Near-Atomic Resolution
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- Weill Cornell Medicine team led by Dr. Alessio Accardi captured high-resolution images of the TMEM16F scramblase by embedding copies of the protein in tiny spheroid liposomes that mimic native cell-membrane environments.
- TMEM16F is a dual-function protein that scrambles membrane lipids and acts as an ion channel; a mutation in it causes Scott Syndrome, a hemophilia-like bleeding disorder.
- The study, published in Nature Structural and Molecular Biology, used cryo-electron microscopy to show the protein's elements rotate into an X-shape in the membrane, with ions moving through its interior while lipids move along its outside.
- Co-first authors Dr. Zhang Feng and Omar Alvarenga led the structural work in the Accardi laboratory, comparing normal and mutated versions of TMEM16F to map its active conformation.
- Accardi said the revealed mechanism is 'strikingly different' from earlier studies of related scramblases, a finding that gives drug developers a concrete target for the first time.
- Therapeutic applications include a TMEM16F activator as a pro-coagulant for Scott Syndrome patients and an inhibitor as an anticoagulant, with potential uses in cancer and infection as well.
Why it matters: Patients with Scott Syndrome and related bleeding disorders gain a concrete drug-design target, since this is the first near-atomic picture of TMEM16F's active form. Drug developers can now design specific activators (pro-coagulants) or inhibitors (anticoagulants) — a level of precision that the protein's structural fragility had previously blocked, according to Accardi's team.
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