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MLKL mixed lineage kinase domain like pseudokinase [ Homo sapiens (human) ]

Gene ID: 197259, updated on 11-Apr-2024

Summary

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Official Symbol
MLKLprovided by HGNC
Official Full Name
mixed lineage kinase domain like pseudokinaseprovided by HGNC
Primary source
HGNC:HGNC:26617
See related
Ensembl:ENSG00000168404 MIM:615153; AllianceGenome:HGNC:26617
Gene type
protein coding
RefSeq status
REVIEWED
Organism
Homo sapiens
Lineage
Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as
hMLKL
Summary
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. 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]
Expression
Broad expression in spleen (RPKM 10.5), bone marrow (RPKM 10.4) and 23 other tissues See more
Orthologs
mouse all
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Genomic context

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Location:
16q23.1
Exon count:
12
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 16 NC_000016.10 (74671855..74700862, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 16 NC_060940.1 (80718597..80747927, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 16 NC_000016.9 (74705753..74734760, complement)

Chromosome 16 - NC_000016.10Genomic Context describing neighboring genes Neighboring gene ring finger and WD repeat domain 3 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7699 Neighboring gene ReSE screen-validated silencer GRCh37_chr16:74715965-74716163 Neighboring gene thymopoietin pseudogene 2 Neighboring gene ReSE screen-validated silencer GRCh37_chr16:74728193-74728362 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11108 Neighboring gene Neanderthal introgressed variant-containing enhancer experimental_44395 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:74763414-74763939 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:74763940-74764464 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr16:74767393-74767952 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:74771195-74771902 Neighboring gene fatty acid 2-hydroxylase Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:74781673-74782338 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:74782339-74783002 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr16:74786737-74787236 Neighboring gene BRD4-independent group 4 enhancer GRCh37_chr16:74793901-74795100 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11109 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 11110 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7700 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7701 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7702 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 7703 Neighboring gene uncharacterized LOC105371343

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • Project title: HPA RNA-seq normal tissues
  • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
  • BioProject: PRJEB4337
  • Publication: PMID 24309898
  • Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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Related articles in PubMed

  1. Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy. Fujita Y, et al. ESC Heart Fail, 2022 Oct. PMID 35851586, Free PMC Article
  2. Rare catastrophes and evolutionary legacies: human germline gene variants in MLKL and the necroptosis signalling pathway. Garnish SE, et al. Biochem Soc Trans, 2022 Feb 28. PMID 35166320, Free PMC Article
  3. Mixed lineage kinase domain-like pseudokinase-mediated necroptosis aggravates periodontitis progression. Yang Y, et al. J Mol Med (Berl), 2022 Jan. PMID 34647144
  4. Positive Charges in the Brace Region Facilitate the Membrane Disruption of MLKL-NTR in Necroptosis. Yang Y, et al. Molecules, 2021 Aug 27. PMID 34500630, Free PMC Article
  5. Mixed Lineage Kinase Domain-Like Pseudokinase (MLKL) Gene Expression in Human Atherosclerosis with and without Type 2 Diabetes Mellitus. Kamal AM, et al. Iran Biomed J, 2021 Jul 1. PMID 34217157, Free PMC Article

See all (109) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis.
    Title: MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis.
  2. MLKL deficiency alleviates neuroinflammation and motor deficits in the alpha-synuclein transgenic mouse model of Parkinson's disease.
    Title: MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson's disease.
  3. Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
    Title: Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
  4. MLKL regulates Cx43 ubiquitinational degradation and mediates neuronal necroptosis in ipsilateral thalamus after focal cortical infarction.
    Title: MLKL regulates Cx43 ubiquitinational degradation and mediates neuronal necroptosis in ipsilateral thalamus after focal cortical infarction.
  5. A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.
    Title: A common human MLKL polymorphism confers resistance to negative regulation by phosphorylation.
  6. Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.
    Title: Skp2-mediated MLKL degradation confers cisplatin-resistant in non-small cell lung cancer cells.
  7. Upregulation of necroptosis markers RIPK3/MLKL and their crosstalk with autophagy-related protein Beclin-1 in primary immune thrombocytopenia.
    Title: Upregulation of necroptosis markers RIPK3/MLKL and their crosstalk with autophagy-related protein Beclin-1 in primary immune thrombocytopenia.
  8. MLKL-Driven Inflammasome Activation and Caspase-8 Mediate Inflammatory Cell Death in Influenza A Virus Infection.
    Title: MLKL-Driven Inflammasome Activation and Caspase-8 Mediate Inflammatory Cell Death in Influenza A Virus Infection.
  9. Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis.
    Title: Surviving death: emerging concepts of RIPK3 and MLKL ubiquitination in the regulation of necroptosis.
  10. Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy.
    Title: Enhanced nuclear localization of phosphorylated MLKL predicts adverse events in patients with dilated cardiomyopathy.
Submit: New GeneRIF Correction See all GeneRIFs (89)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

EBI GWAS Catalog

Description
Meta-analysis identifies four new loci associated with testicular germ cell tumor.
EBI GWAS Catalog

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Pathways from PubChem

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Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Clone Names

  • FLJ34389

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables ATP binding IDA
Inferred from Direct Assay
more info
 PubMed 
enables protein binding IPI
Inferred from Physical Interaction
more info
 PubMed 
NOT enables protein kinase activity ISS
Inferred from Sequence or Structural Similarity
more info
  
enables protein kinase binding IEA
Inferred from Electronic Annotation
more info
  
NOT enables protein serine/threonine kinase activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables protein-containing complex binding IDA
Inferred from Direct Assay
more info
 PubMed 
Process Evidence Code Pubs
involved_in cell surface receptor signaling pathway IEA
Inferred from Electronic Annotation
more info
  
involved_in defense response to virus ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in execution phase of necroptosis IDA
Inferred from Direct Assay
more info
 PubMed 
involved_in execution phase of necroptosis ISS
Inferred from Sequence or Structural Similarity
more info
  
involved_in necroptotic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in necroptotic signaling pathway IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in necroptotic signaling pathway IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in protein homotrimerization IDA
Inferred from Direct Assay
more info
 PubMed 
Component Evidence Code Pubs
located_in cell junction IDA
Inferred from Direct Assay
more info
  
is_active_in cytoplasm IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in cytoplasm IDA
Inferred from Direct Assay
more info
 PubMed 
located_in cytosol IDA
Inferred from Direct Assay
more info
  
located_in cytosol TAS
Traceable Author Statement
more info
  
located_in nucleus ISS
Inferred from Sequence or Structural Similarity
more info
  
located_in plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 

General protein information

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Preferred Names
mixed lineage kinase domain-like protein

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

mRNA and Protein(s)

  1. NM_001142497.3 → NP_001135969.1  mixed lineage kinase domain-like protein isoform 2

    See identical proteins and their annotated locations for NP_001135969.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2, also known as MLKLshRNA-B) lacks several consecutive exons in the mid region and uses an alternate donor splice site at the next exon, which causes a localized frameshift compared to variant 1. The resulting isoform (2) has the same N- and C-termini but is shorter, lacking an internal protein segment compared to isoform 1.
    Source sequence(s)
    BC028141, BQ575071, DB291522
    Consensus CDS
    CCDS45528.1
    UniProtKB/Swiss-Prot
    Q8NB16
    Related
    ENSP00000303118.7, ENST00000306247.11
    Conserved Domains (1) summary
    PHA02988
    Location:212 → 261
    PHA02988; hypothetical protein; Provisional

  2. NM_152649.4 → NP_689862.1  mixed lineage kinase domain-like protein isoform 1

    See identical proteins and their annotated locations for NP_689862.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1, also known as MLKLshRNA-A) represents the longer transcript and encodes the longer isoform (1).
    Source sequence(s)
    AK091708, BC028141, BQ575071
    Consensus CDS
    CCDS32487.1
    UniProtKB/Swiss-Prot
    A6NCE4, Q8N6V0, Q8NB16
    UniProtKB/TrEMBL
    Q5JPC5
    Related
    ENSP00000308351.7, ENST00000308807.12
    Conserved Domains (2) summary
    PHA02988
    Location:177 → 469
    PHA02988; hypothetical protein; Provisional
    cl21453
    Location:215 → 466
    PKc_like; Protein Kinases, catalytic domain

RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p14 Primary Assembly

Genomic

  1. NC_000016.10 Reference GRCh38.p14 Primary Assembly

    Range
    74671855..74700862 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_005255834.5 → XP_005255891.1  mixed lineage kinase domain-like protein isoform X1

    See identical proteins and their annotated locations for XP_005255891.1

    UniProtKB/Swiss-Prot
    A6NCE4, Q8N6V0, Q8NB16
    UniProtKB/TrEMBL
    Q5JPC5
    Conserved Domains (2) summary
    PHA02988
    Location:177 → 469
    PHA02988; hypothetical protein; Provisional
    cl21453
    Location:215 → 466
    PKc_like; Protein Kinases, catalytic domain

  2. XM_047433704.1 → XP_047289660.1  mixed lineage kinase domain-like protein isoform X2

  3. XM_047433710.1 → XP_047289666.1  mixed lineage kinase domain-like protein isoform X8

  4. XM_047433707.1 → XP_047289663.1  mixed lineage kinase domain-like protein isoform X5

  5. XM_047433705.1 → XP_047289661.1  mixed lineage kinase domain-like protein isoform X3

  6. XM_047433708.1 → XP_047289664.1  mixed lineage kinase domain-like protein isoform X6

  7. XM_047433709.1 → XP_047289665.1  mixed lineage kinase domain-like protein isoform X7

  8. XM_047433706.1 → XP_047289662.1  mixed lineage kinase domain-like protein isoform X4

  9. XM_011522936.3 → XP_011521238.1  mixed lineage kinase domain-like protein isoform X7

    See identical proteins and their annotated locations for XP_011521238.1

    Conserved Domains (1) summary
    cl21453
    Location:215 → 277
    PKc_like; Protein Kinases, catalytic domain

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060940.1 Alternate T2T-CHM13v2.0

    Range
    80718597..80747927 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054379744.1 → XP_054235719.1  mixed lineage kinase domain-like protein isoform X1

    UniProtKB/Swiss-Prot
    A6NCE4, Q8N6V0, Q8NB16

  2. XM_054379745.1 → XP_054235720.1  mixed lineage kinase domain-like protein isoform X2

  3. XM_054379752.1 → XP_054235727.1  mixed lineage kinase domain-like protein isoform X8

  4. XM_054379748.1 → XP_054235723.1  mixed lineage kinase domain-like protein isoform X5

  5. XM_054379746.1 → XP_054235721.1  mixed lineage kinase domain-like protein isoform X3

  6. XM_054379749.1 → XP_054235724.1  mixed lineage kinase domain-like protein isoform X6

  7. XM_054379750.1 → XP_054235725.1  mixed lineage kinase domain-like protein isoform X7

  8. XM_054379747.1 → XP_054235722.1  mixed lineage kinase domain-like protein isoform X4

  9. XM_054379751.1 → XP_054235726.1  mixed lineage kinase domain-like protein isoform X7

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
Q8NB16.1 GenPept UniProtKB/Swiss-Prot:Q8NB16

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