The significance of protein kinases in modulation of signalling pathways through phosphorylation of substrates is well documented, however the importance of non-catalytic functions are becoming increasingly recognised. This is highlighted by the existence of a subclass of protein kinases known as pseudokinases, which despite deficiencies in performing phosphotransfer reactions, participate in diverse intracellular pathways by acting as scaffolds, signalling integrators and allosteric modulators of protein activity.
These principles are exemplified by the pseudokinase Mixed Lineage Kinase domain-Like (MLKL). MLKL is the most downstream known effector in the cell death pathway called necroptosis: an inflammatory form of cell death that has been implicated in a range of different diseases including neurodegenerative diseases, autoimmune diseases, and the cell death associated with heart attack and stroke. The role of MLKL in this pathway has only been known for five years, however during this time there has been increasing evidence that MLKL acts as a molecular switch, and undergoes a conformational change on phosphorylation by the upstream regulatory kinase Receptor Interacting Protein Kinase 3 (RIPK3). We believe this conformational change transforms MLKL from a benign intracellular protein to a killer pseudokinase, and allows the permeabilisation of membranes necessary to induce necroptotic cell death.
In addition to serving functions as a molecular switch function and a suppressor of the killing function mediate by its adjacent four-helix bundle domain, the MLKL pseudokinase domain has recently been revealed to serve an adaptor domain. Here, we describe our current understanding of the MLKL pseudokinase domain’s functions, including its recently uncovered reliance on the molecular chaperone HSP90 to mediate cell death. These data provide additional insight on the role of MLKL in necroptosis and, more broadly, the function of pseudokinases in signalling pathways.