Mixed lineage kinase domain like pseudokinase

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

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) Band 16q23.1 Start 74,671,855 bp End 74,700,960 bp
Gene location (Mouse) Chr. Chromosome 8 (mouse) Band 8|8 E1 Start 112,038,429 bp End 112,064,809 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in monocyte blood spleen upper lobe of left lung appendix right lung pancreatic epithelial cell bone marrow bone marrow cells trabecular bone Top expressed in bone marrow epithelium of stomach duodenum Paneth cell subcutaneous adipose tissue colon jejunum white adipose tissue cervix left colon More reference expression data BioGPS n/a
Gene ontology Molecular function nucleotide binding protein binding ATP binding protein kinase binding protein kinase activity identical protein binding signal transducer activity protein-containing complex binding protein serine/threonine kinase activity JUN kinase kinase kinase activity Cellular component cytoplasm cytosol plasma membrane membrane Biological process necroptosis protein homotrimerization programmed cell death protein phosphorylation intracellular signal transduction cell surface receptor signaling pathway MAPK cascade Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 197259 74568 Ensembl ENSG00000168404 ENSMUSG00000012519 UniProt Q8NB16 Q9D2Y4 RefSeq (mRNA) NM_001142497 NM_152649 NM_029005 NM_001310613 RefSeq (protein) NP_001135969 NP_689862 NP_001297542 NP_083281 Location (UCSC) Chr 16: 74.67 – 74.7 Mb Chr 8: 112.04 – 112.06 Mb PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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

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 (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. S2CID 17832872.
• 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. Bibcode:2012PNAS..109.5322Z. 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. PMC 8369836. PMID 24316671. S2CID 27124722.
• 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. S2CID 25540582.
• 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.