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Anoctamin-6 (TMEM16F) is a calcium-activated protein that functions as both a phospholipid scramblase and a non-selective ion channel [1, 3, 10]. It plays a pivotal role in blood coagulation by externalizing phosphatidylserine (PS) on the surface of activated platelets, providing a scaffold for the assembly of procoagulant complexes [6, 9]. Mutations in the TMEM16F gene cause Scott syndrome, a rare bleeding disorder characterized by defective PS exposure [8, 14]. Beyond hemostasis, TMEM16F is involved in bone mineralization, membrane repair, and viral-induced cell fusion, notably in SARS-CoV-2 infection where it facilitates syncytia formation [7, 11, 14]. Pharmacological targeting of TMEM16F with inhibitors like niclosamide has shown promise in treating COVID-19 and potentially preventing thrombosis or neurodegeneration [3, 11, 13, 15]. Conversely, its activation by certain drugs like SSRIs may increase bleeding risks, highlighting its importance in clinical safety and therapeutic development [2].
Inhibition of calcium-activated phospholipid scrambling and ion channel activity by binding to the TM1-TM6 hydrophobic groove [3, 12, 15]
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