Protein shapeshifting in necroptotic cell death signaling

Necroptosis is a mode of programmed cell death executed by the mixed lineage kinase domain-like (MLKL) pseudokinase following its activation by the upstream receptor-interacting protein kinase-3 (RIPK3), subsequent to activation of death, Toll-like, and pathogen receptors. The pathway originates in innate immunity, although interest has surged in therapeutically targeting necroptosis owing to its dysregulation in inflammatory diseases. Here, we explore how protein conformation and higher order assembly of the pathway effectors – Z-DNA-binding protein-1 (ZBP1), RIPK1, RIPK3, and MLKL – can be modulated by post-translational modifications, such as phosphorylation, ubiquitylation, and lipidation, and intermolecular interactions to tune activities and modulate necroptotic signaling flux. As molecular level knowledge of cell death signaling grows, we anticipate targeting the conformations of key necrosomal effector proteins will emerge as new avenues for drug development.