Mixed lineage kinase domain like pseudokinase

Protein-coding gene in the species Homo sapiens
MLKL
Available structures
PDBOrtholog search: PDBe RCSB
List of PDB id codes

2MSV, 4M67, 4MWI

Identifiers
AliasesMLKL, hmixed lineage kinase domain-like, mixed lineage kinase domain like pseudokinase
External IDsOMIM: 615153; MGI: 1921818; HomoloGene: 77416; GeneCards: MLKL; OMA:MLKL - orthologs
Gene location (Human)
Chromosome 16 (human)
Chr.Chromosome 16 (human)[1]
Chromosome 16 (human)
Genomic location for MLKL
Genomic location for MLKL
Band16q23.1Start74,671,855 bp[1]
End74,700,960 bp[1]
Gene location (Mouse)
Chromosome 8 (mouse)
Chr.Chromosome 8 (mouse)[2]
Chromosome 8 (mouse)
Genomic location for MLKL
Genomic location for MLKL
Band8|8 E1Start112,038,429 bp[2]
End112,064,809 bp[2]
RNA expression pattern
Bgee
HumanMouse (ortholog)
Top expressed in
  • granulocyte

  • monocyte

  • blood

  • spleen

  • upper lobe of left lung

  • appendix

  • myocardium of left ventricle

  • right lung

  • pancreatic epithelial cell

  • mucosa of ileum
Top expressed in
  • bone marrow

  • epithelium of stomach

  • stroma of bone marrow

  • endothelial cell of lymphatic vessel

  • duodenum

  • transitional epithelium of urinary bladder

  • Paneth cell

  • subcutaneous adipose tissue

  • colon

  • jejunum
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
SpeciesHumanMouse
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 MbChr 8: 112.04 – 112.06 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/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]. 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.[6]

See also

References

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000168404 – Ensembl, May 2017
  2. ^ a b c 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.
  5. ^ "Entrez Gene: Mixed lineage kinase domain like pseudokinase". Retrieved 2017-12-31.
  6. ^ Faergeman SL, Evans H, Attfield KE, Desel C, Kuttikkatte SB, Sommerlund M, et al. (2020). "A novel neurodegenerative spectrum disorder in patients with MLKL deficiency". Cell Death & Disease. 11 (5). doi:10.1038/s41419-020-2494-0. PMC 7195448. PMID 32358523. Art. No. 303.

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.


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