1.A.105 The Mixed Lineage Kinase Domain-like (MLKL) Family 

The mixed lineage kinase domain-like (MLKL) protein is a key factor in tumor necrosis factor-induced necroptosis. Studies on necroptosis execution revealed a commitment role of MLKL in membrane disruption. Xia et al. 2016 demonstrated that MLKL forms cation channels that are permeable preferentially to Mg²⁺ rather than Ca²⁺ in the presence of Na⁺ and K⁺. Moreover, the N-terminal domain containing six helices (H1-H6) is sufficient to form channels. Using the substituted cysteine accessibility method, helix H1, H2, H3, H5 and H6 appeared to be transmembrane segments, while H4 is located in the cytoplasm. Finally, MLKL-induced membrane depolarization and cell death exhibit a positive correlation to its channel activity. The Mg²⁺-preferred permeability and five transmembrane segment topology distinguish MLKL from previously identified Mg²⁺-permeable channels and thus establish MLKL as a novel class of cation channels.