MLKL oligomerizes

Stable Identifier
R-HSA-5357927
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Mixed lineage kinase domain-like protein (MLKL) was found to form oligomers (detected as homotrimers) when it was overexpressed in human embryonic kidney 293 (HEK293) cells (Cai Z et al. 2014). The oligomerization of MLKL was also observed in multiple human (colon adenocarcinoma HT29, FADD-null Jurkat cells, leukemic monocyte lymphoma U937) and mouse cells upon (TNF+Smac mimetic+caspase inhibitor z-VAD-FMK)-induced necroptosis (Cai Z et al. 2014; Chen X et al. 2014). Whether MLKL forms trimers, tetramers or higher molecular structures, remains to be clarified (Cai Z et al. 2014; Chen X et al. 2014; Dondelinger Y et al. 2014; Wang H et al. 2014). The oligomerization of MLKL was blocked by reducing agents such as dithiothreitol or beta-mercaptoethanol, suggesting that oligomeric forms are probably stabilized by disulphide bonds (Cai Z et al. 2014; Wang H et al. 2014). Oligomeric MLKL was not detected in cell lysates of HEK293 cells that were transfected with kinase-dead RIPK3 and MLKL (Cai Z et al. 2014). Mutations in phosphorylation sites of MLKL also blocked MLKL oligomerization (Cai Z et al. 2014; Wang H et al. 2014). Moreover, gel filtration chromatography analysis of recombinant wild-type or phosphorylation site mutant MLKL proteins is in agreement with immunoblotting data, confirming that RIPK3-mediated phosphorylation of MLKL promotes oligomerization of MLKL (Wang H et al. 2014). Oligomers of MLKL translocate to membrane compartments(Cai Z et al. 2014; Dondelinger Y et al. 2014; Wang H et al. 2014).

Even though the stoichiometry of the MLKL oligomerization in the Reactome event depicts MLKL homotrimer, it remains unclear whether MLKL forms trimers, tetramers or higher molecular structure (Cai Z et al. 2014; Chen X et al. 2014; Dondelinger Y et al. 2014; Wang H et al. 2014).

Literature References
PubMed ID Title Journal Year
24703947 Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3

Wang, H, Sun, L, Su, L, Rizo, J, Liu, L, Wang, LF, Wang, FS, Wang, X

Mol. Cell 2014
24316671 Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis

Cai, Z, Jitkaew, S, Zhao, J, Chiang, HC, Choksi, S, Liu, J, Ward, Y, Wu, LG, Liu, ZG

Nat. Cell Biol. 2014
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