Mixed lineage kinase domain like pseudokinase explained

Mixed lineage kinase domain like pseudokinase (MLKL) is a protein that in humans is encoded by the MLKL gene.^[1]

Function

This gene belongs to the protein kinase superfamily. The encoded protein contains a protein kinase-like domain; however, is thought to be inactive because it lacks several residues required for activity. This protein plays a critical role in tumor necrosis factor (TNF)-induced necroptosis, a programmed cell death process, via interaction with receptor-interacting protein 3 (RIP3), which is a key signaling molecule in necroptosis pathway. Inhibitor studies and knockdown of this gene inhibited TNF-induced necrosis.

Influence in diseases

High levels of this protein and RIP3 are associated with inflammatory bowel disease in children. Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2015]. A unique neurodegenerative disease has been reported in association with a homozygous frameshift mutation, rs561839347, in MLKL that causes replacement of part of the C-terminal pseudokinase domain with a 21-residue sequence of random amino acids.^[2]

See also

• Necroptosis
• Cell death

Further reading

• Dastani Z, Pajukanta P, Marcil M, Rudzicz N, Ruel I, Bailey SD, Lee JC, Lemire M, Faith J, Platko J, Rioux J, Hudson TJ, Gaudet D, Engert JC, Genest J . Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects . Eur. J. Hum. Genet. . 18 . 3 . 342–7 . 2010 . 19844255 . 2824775 . 10.1038/ejhg.2009.157 .
• Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X . Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase . Cell . 148 . 1–2 . 213–27 . 2012 . 22265413 . 10.1016/j.cell.2011.11.031 . 17832872 . free .
• Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, Liu ZG . Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis . Proc. Natl. Acad. Sci. U.S.A. . 109 . 14 . 5322–7 . 2012 . 22421439 . 3325682 . 10.1073/pnas.1200012109 . 2012PNAS..109.5322Z . free .
• Chen W, Zhou Z, Li L, Zhong CQ, Zheng X, Wu X, Zhang Y, Ma H, Huang D, Li W, Xia Z, Han J . Diverse sequence determinants control human and mouse receptor interacting protein 3 (RIP3) and mixed lineage kinase domain-like (MLKL) interaction in necroptotic signaling . J. Biol. Chem. . 288 . 23 . 16247–61 . 2013 . 23612963 . 3675564 . 10.1074/jbc.M112.435545 . free .
• Colbert LE, Fisher SB, Hardy CW, Hall WA, Saka B, Shelton JW, Petrova AV, Warren MD, Pantazides BG, Gandhi K, Kowalski J, Kooby DA, El-Rayes BF, Staley CA, Adsay NV, Curran WJ, Landry JC, Maithel SK, Yu DS . Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma . Cancer . 119 . 17 . 3148–55 . 2013 . 23720157 . 4389890 . 10.1002/cncr.28144 .
• Murphy JM, Lucet IS, Hildebrand JM, Tanzer MC, Young SN, Sharma P, Lessene G, Alexander WS, Babon JJ, Silke J, Czabotar PE . Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL . Biochem. J. . 457 . 3 . 369–77 . 2014 . 24219132 . 10.1042/BJ20131270 .
• Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, Ward Y, Wu LG, Liu ZG . Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis . Nat. Cell Biol. . 16 . 1 . 55–65 . 2014 . 24316671 . 10.1038/ncb2883 . 27124722 . 8369836 .
• Pierdomenico M, Negroni A, Stronati L, Vitali R, Prete E, Bertin J, Gough PJ, Aloi M, Cucchiara S . Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation . Am. J. Gastroenterol. . 109 . 2 . 279–87 . 2014 . 24322838 . 10.1038/ajg.2013.403 . 25540582 .
• Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X . Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3 . Mol. Cell . 54 . 1 . 133–146 . 2014 . 24703947 . 10.1016/j.molcel.2014.03.003 . free .

Notes and References

1. Web site: Entrez Gene: Mixed lineage kinase domain like pseudokinase. 2017-12-31.
2. Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, Jensen LT, Frokiaer J, Friese MA, Matthews PM, Luchtenborg C, Brügger B, Oturai AB, Dendrou CA, Fugger L. 6. A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death & Disease. 11. 5. Art. No. 303. 2020. 10.1038/s41419-020-2494-0. free. 32358523. 7195448.