Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis

Necroptosis is a lytic form of programmed cell death implicated in inflammatory pathologies, leading to intense interest in the underlying mechanisms and therapeutic prospects. Here, we review our current structural understanding of how the terminal executioner of the pathway, the dead kinase, mixed lineage kinase domain-like (MLKL), is converted from a dormant to killer form by the upstream regulatory kinase, RIPK3. RIPK3-mediated phosphorylation of MLKL's pseudokinase domain toggles a molecular switch that induces dissociation from a cytoplasmic platform, assembly of MLKL oligomers, and trafficking to the plasma membrane, where activated MLKL accumulates and permeabilises the lipid bilayer to induce cell death. We highlight gaps in mechanistic knowledge of MLKL's activation, how mechanisms diverge between species, and the power of modelling in advancing structural insights.