Mixed lineage kinase domain like pseudokinase

MLKL
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2MSV, 4M67, 4MWI
Identifiers
Aliases	MLKL, hmixed lineage kinase domain-like, mixed lineage kinase domain like pseudokinase
External IDs	OMIM: 615153 MGI: 1921818 HomoloGene: 77416 GeneCards: MLKL
Gene location (Human)
Chr.	Chromosome 16 (human)[1]
End	74,700,960 bp[1]
Gene location (Mouse)
Chr.	Chromosome 8 (mouse)[2]
End	111,338,177 bp[2]
Gene ontology
Molecular function	• nucleotide binding; • GO:0001948 protein binding; • ATP binding; • protein kinase binding; • protein kinase activity; • identical protein binding; • signal transducer activity; • GO:0032403 macromolecular complex binding; • protein serine/threonine kinase activity; • JUN kinase kinase kinase activity;
Cellular component	• cytoplasm; • cytosol; • cell membrane; • membrane;
Biological process	• necroptosis; • protein homotrimerization; • programmed cell death; • protein phosphorylation; • intracellular signal transduction; • cell surface receptor signaling pathway; • MAPK cascade; • activation of JNKK activity; • activation of JUN kinase activity;
	Sources:Amigo / QuickGO
Orthologs
	197259
	74568
	ENSG00000168404
	ENSMUSG00000012519
	Q8NB16
	Q9D2Y4
	NM_001142497; NM_152649
	NM_029005; NM_001310613
	NP_001135969; NP_689862
	NP_001297542; NP_083281
	Wikidata
View/Edit Human	View/Edit Mouse

Mixed lineage kinase domain like pseudokinase (MLKL) is a protein that in humans is encoded by the MLKL gene. [5]

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]. Some reports have linked it to unusual variants of multiple sclerosis[6]

References

GRCh38: Ensembl release 89: ENSG00000168404 - Ensembl, May 2017
GRCm38: Ensembl release 89: ENSMUSG00000012519 - Ensembl, May 2017
"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
"Entrez Gene: Mixed lineage kinase domain like pseudokinase". Retrieved 2017-12-31.
Faergeman, S.L., Evans, H., Attfield, K.E. et al. A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death Dis 11, 303 (2020). https://doi.org/10.1038/s41419-020-2494-0

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 (2010). "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. doi:10.1038/ejhg.2009.157. PMC 2824775. PMID 19844255.
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, Wang L, Yan J, Liu W, Lei X, Wang X (2012). "Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase". Cell. 148 (1–2): 213–27. doi:10.1016/j.cell.2011.11.031. PMID 22265413.
Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, Liu ZG (2012). "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. doi:10.1073/pnas.1200012109. PMC 3325682. PMID 22421439.
Chen W, Zhou Z, Li L, Zhong CQ, Zheng X, Wu X, Zhang Y, Ma H, Huang D, Li W, Xia Z, Han J (2013). "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. doi:10.1074/jbc.M112.435545. PMC 3675564. PMID 23612963.
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 (2013). "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. doi:10.1002/cncr.28144. PMC 4389890. PMID 23720157.
Murphy JM, Lucet IS, Hildebrand JM, Tanzer MC, Young SN, Sharma P, Lessene G, Alexander WS, Babon JJ, Silke J, Czabotar PE (2014). "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. doi:10.1042/BJ20131270. PMID 24219132.
Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, Ward Y, Wu LG, Liu ZG (2014). "Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis". Nat. Cell Biol. 16 (1): 55–65. doi:10.1038/ncb2883. PMID 24316671.
Pierdomenico M, Negroni A, Stronati L, Vitali R, Prete E, Bertin J, Gough PJ, Aloi M, Cucchiara S (2014). "Necroptosis is active in children with inflammatory bowel disease and contributes to heighten intestinal inflammation". Am. J. Gastroenterol. 109 (2): 279–87. doi:10.1038/ajg.2013.403. PMID 24322838.
Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, Wang FS, Wang X (2014). "Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3". Mol. Cell. 54 (1): 133–146. doi:10.1016/j.molcel.2014.03.003. PMID 24703947.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000168404 - Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000012519 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[entrez-5] "Entrez Gene: Mixed lineage kinase domain like pseudokinase". Retrieved 2017-12-31.

[6] Faergeman, S.L., Evans, H., Attfield, K.E. et al. A novel neurodegenerative spectrum disorder in patients with MLKL deficiency. Cell Death Dis 11, 303 (2020). https://doi.org/10.1038/s41419-020-2494-0

Mixed lineage kinase domain like pseudokinase

Function

Influence in diseases

See also

References

Further reading