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Uncovering human mixed lineage kinase domain-like activation in necroptosis
Cristina D Guibao1, Katherine Petrinjak1, Tudor Moldoveanu1
1Departments of Structural Biology & Chemical Biology & Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
Abstract:
MLKL and its obligate upstream receptor interacting protein kinase 3 are essential components of necroptosis. It is well established that MLKL is the executioner of plasma membrane rupture in necroptosis. In healthy cells MLKL is dormant. Several dormant configurations have emerged from high-resolution structural studies revealing distinct mechanisms of MLKL autoinhibition in mammals. MLKL is activated through the concerted actions of receptor interacting protein kinase 3, which phosphorylates MLKL, and, in the case of the human pathway, inositol phosphate (IP) metabolites synthesized by the IP kinases of the IP metabolic pathway. Here, we highlight recent progress toward understanding the mechanisms of regulation of human MLKL, and survey the latest opportunities for targeting MLKL in pathophysiology.
Insights
Mixed lineage kinase domain-like pseudokinase (MLKL) executes necroptosis by rupturing the plasma membrane. Its activation involves receptor interacting protein kinase 3 and inositol phosphate metabolites, offering therapeutic targets.
Area of Science:
- Molecular Biology
- Cell Death Pathways
- Biochemistry
Background:
- Mixed lineage kinase domain-like pseudokinase (MLKL) is a key executioner of necroptosis, a programmed form of cell death.
- MLKL's dormant state in healthy cells is maintained by distinct autoinhibition mechanisms, elucidated through structural studies.
- Receptor interacting protein kinase 3 (RIPK3) is an essential upstream regulator of MLKL activation.
Purpose of the Study:
- To review recent advancements in understanding the regulatory mechanisms of human MLKL.
- To explore potential therapeutic strategies targeting MLKL in various pathological conditions.
- To elucidate the role of inositol phosphate (IP) metabolites in MLKL activation.
Main Methods:
- High-resolution structural studies to determine MLKL's dormant configurations.
- Analysis of phosphorylation events mediated by RIPK3.
- Investigation of the role of IP metabolites in the human necroptosis pathway.
Main Results:
- Multiple autoinhibited structures of MLKL reveal diverse mechanisms of self-regulation.
- RIPK3-mediated phosphorylation is crucial for MLKL activation.
- Inositol phosphate metabolites are required for human MLKL activation, highlighting the IP metabolic pathway's role.
Conclusions:
- Understanding MLKL's regulation provides insights into necroptosis execution.
- Targeting MLKL and its regulatory pathways presents promising therapeutic opportunities for diseases involving necroptosis.
- The interplay between RIPK3 and IP metabolites is critical for activating the necroptosis executioner, MLKL.
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