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).
Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:23835476, PubMed:24012422, PubMed:24019532, PubMed:27321907, 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:24012422, PubMed:24019532, PubMed:27321907). 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).
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).
Belongs to the protein kinase superfamily.
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.
Mixed lineage kinase domain-like protein, Mlkl
Proteins
Immunology & Infectious Disease
54317Da
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