Calcium (Ca2+)-activated ion channels and lipid scramblases in the transmembrane protein 16 (TMEM16) family are structurally related to mechanosensitive ion channels in the TMEM63 and transmembrane channel-like (TMC) families. Members of this structurally related superfamily share similarities in gating transitions and serve a wide range of physiological functions, which is evident from their disease associations. The TMEM16, TMEM63 and TMC families include members with important functions in the cell membrane and/or intracellular organelles such as the endoplasmic reticulum, membrane contact sites, endosomes and lysosomes. Moreover, some members of the TMEM16 family and the TMC family perform dual functions of ion channel and lipid scramblase, leading to intriguing physiological implications. In addition to their physiological functions such as mediating phosphatidylserine exposure and facilitation of extracellular vesicle generation and cell fusion, scramblases are involved in the entry and replication of enveloped viruses. Comparisons of structurally diverse scramblases may uncover features in the lipid-scrambling mechanisms that are likely shared by scramblases.
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