Conformational interconversion of MLKL and disengagement from RIPK3 precede cell death by necroptosis

Mixed Lineage Kinase Domain-Like (MLKL) pseudokinase is phosphorylated by RIPK3 kinase Oral Irrigators prior to cell death by necroptosis.Here, the authors use monobodies that bind to the MLKL pseudokinase domain as tools, which allowed them to determine the crystal structures of the MLKL pseudokinase domain in two distinct conformations.By combining their structural data with cell signalling assays and MD simulations they provide CINNAMON TOOTHPASTE evidence that endogenous MLKL preassociates with its upstream regulator RIPK3, and that MLKL disengages from RIPK3 following the induction of necroptosis.