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Medical Sciences

Necroptosis: MLKL Polymerization


Andrea Johnston and Zhigao Wang

Necroptosis is a subtype of regulated necrosis that occurs when caspases are inhibited or fail to activate. Stimulus of cell death receptors results in a signaling cascade that triggers caspase independent, immunogenic cell death. The core pathway relies on Receptor Interacting Protein Kinase (RIPK) 1 and 3, which interact through their Receptor Homotypic Interacting Motif (RHIM) domains, and form an amyloid-like structure termed the necrosome. RIPK3 recruits and phosphorylates Mixed Lineage Kinase domain-Like pseudokinase (MLKL), the terminal mediator in the necroptotic pathway. MLKL polymerizes to form a second amyloid-like structure that causes cell membrane disruption resulting in cell death. Although the core necroptosis pathway has been elucidated, the details of MLKL membrane translocation and membrane disruption remain an open area of research.
 
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