Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:23835476, PubMed:27321907, PubMed:24012422, PubMed:24019532, PubMed:32200799, PubMed:32296175). Does not have protein kinase activity (PubMed:24012422). Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage (PubMed:23835476, PubMed:27321907, PubMed:24012422, PubMed:24019532). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (PubMed:32200799, PubMed:32296175). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (By similarity). Activated via binding to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which mediates the release of an N-terminal auto-inhibitory region (By similarity). Activation requires not only RIPK3-dependent phosphorylation but also binding to highly phosphorylated inositol phosphates (By similarity). Homooligomer (By similarity). Homotrimer; forms homotrimers on necroptosis induction (By similarity). Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3 (By similarity). Within this complex, may play a role in the proper targeting of RIPK1-RIPK3 to its downstream effector PGAM5 (By similarity). Interacts with RIPK3; the interaction is direct and promotes its phosphorylation and subsequent activation (PubMed:22265413, PubMed:23612963, PubMed:27321907, PubMed:24012422, PubMed:24095729). Localizes to the cytoplasm and translocates to the plasma membrane on necroptosis induction (By similarity). Localizes to the nucleus in response to orthomyxoviruses infection (PubMed:32200799). Highly expressed in thymus, colon, intestine, liver, spleen and lung. Expressed at much lower level in skeletal muscle, heart and kidney. Not detected in brain. The coiled coil region 2 is responsible for homotrimerization. The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys-219 and Gln-343 residues (PubMed:24012422, PubMed:24095729). Upon phosphorylation by RIPK3, undergoes an active conformation (PubMed:24012422, PubMed:24095729). Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis (PubMed:24012422, PubMed:24095729, PubMed:32200799). It also induces homotrimerization and localization to the plasma membrane (By similarity). No visible phenotype: mice are viable, fertile and do not developmental or homeostatic phenotype in the absence of overt stress (PubMed:23835476, PubMed:24012422). However, these mice are resistant to TNF-induced necroptosis (PubMed:23835476, PubMed:24012422). At a modestly lethal dose of influenza A virus (IAV), mice do not display increased rates of mortality (PubMed:27321907, PubMed:32200799). Perinatal lethality observed in Ripk1 knockout mice is rescued in knockout mice lacking both Ripk1 and Mlkl (PubMed:27819681). In contrast to human protein, not inhibited by necrosulfonamide, because a Trp residue is present instead of a Cys in position 85. Interaction with RIPK3 is species specific: mouse MLKL only interacts with mouse RIPK3 and not human RIPK3. Belongs to the protein kinase superfamily.