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Description

Mixed lineage kinase domain-like protein (UniProt: Q8NB16, also known as hMLKL) is encoded by the MLKL gene (Gene ID: 197259) in human. MLKL is a pseudokinase that is a terminal protein in the pro-inflammatory necroptotic cell death program. It plays a critical role in TNFa-induced necroptosis. Although it contains a protein kinase domain (aa 194-469), it lacks several residues that are essential for protein kinase activity. It is activated following phosphorylation at Thr357/Ser358 by RIPK3, which leads to its homotrimerization and localization to the plasma membrane where it binds to highly phosphorylated inositol (InsP6) and cardiolipin and disrupts membrane integrity to cause necrotic cell death. Under basal conditions, MLKL is shown to reside in small puncta that are distributed evenly throughout the cytoplasm, but it is detected in plasma membrane shortly after its phosphorylation. It contains two coiled coil regions (aa 55-84 and 139-180). The second coiled coil region is responsible for its oligomerization. MLKL is also reported to be involved in endosomal trafficking, independently of induction of necroptosis, whereby it enhances degradation of receptors and ligands. Two isoforms of MLKL have been described that are produced by alternative splicing. (Ref.: Samson, AL., et al. (2020). Nat. Commun. 11(1), 3151, Yoon, S., et al. (2017). Immunity. 47(1), 51-65, Wang, H., et al (2014). Mol. Cell 54(1), 133-146).