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

    Gene ID: 197259, updated on 10-Dec-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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    See MLKL in Genome Data Viewer
    Location:
    16q23.1
    Exon count:
    12
    Annotation release Status Assembly Chr Location
    RS_2024_08 current GRCh38.p14 (GCF_000001405.40) 16 NC_000016.10 (74671855..74700862, complement)
    RS_2024_08 current T2T-CHM13v2.0 (GCF_009914755.1) 16 NC_060940.1 (80718597..80747927, complement)
    RS_2024_09 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: Tissue-specific circular RNA induction during human fetal development
    • Description: 35 human fetal samples from 6 tissues (3 - 7 replicates per tissue) collected between 10 and 20 weeks gestational time were sequenced using Illumina TruSeq Stranded Total RNA
    • BioProject: PRJNA270632
    • Publication: PMID 26076956
    • Analysis date: Mon Apr 2 22:54:59 2018

    Bibliography

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    Related articles in PubMed

    1. A rare variant in MLKL confers susceptibility to ApoE ɛ4-negative Alzheimer's disease in Hong Kong Chinese population. Wang B, et al. Neurobiol Aging, 2018 Aug. PMID 29656768
    2. The MLKL kinase-like domain dimerization is an indispensable step of mammalian MLKL activation in necroptosis signaling. Zhang Y, et al. Cell Death Dis, 2021 Jun 22. PMID 34158471, Free PMC Article
    3. A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes. Hildebrand JM, et al. Cell Death Dis, 2021 Apr 1. PMID 33795639, Free PMC Article
    4. MLKL: Functions beyond serving as the Executioner of Necroptosis. Zhan C, et al. Theranostics, 2021. PMID 33754026, Free PMC Article
    5. Locking mixed-lineage kinase domain-like protein in its auto-inhibited state prevents necroptosis. Rübbelke M, et al. Proc Natl Acad Sci U S A, 2020 Dec 29. PMID 33318170, Free PMC Article

    See all (123) citations in PubMed

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?
    1. Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis.
      Title: Death at a funeral: Activation of the dead enzyme, MLKL, to kill cells by necroptosis.
    2. MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy.
      Title: MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy.
    3. Necroptosis executioner MLKL plays pivotal roles in agonist-induced platelet prothrombotic responses and lytic cell death in a temporal order.
      Title: Necroptosis executioner MLKL plays pivotal roles in agonist-induced platelet prothrombotic responses and lytic cell death in a temporal order.
    4. MLKL regulates radiation-induced death in breast cancer cells: an interplay between apoptotic and necroptotic signals.
      Title: MLKL regulates radiation-induced death in breast cancer cells: an interplay between apoptotic and necroptotic signals.
    5. MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis.
      Title: MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis.
    6. 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.
    7. Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
      Title: Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
    8. 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.
    9. 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.
    10. 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.
    Submit: New GeneRIF Correction See all GeneRIFs (93)

    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)

    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 identical protein binding IPI
    Inferred from Physical Interaction
    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_2024_08

    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

      UniProtKB/TrEMBL
      Q5JPC5

    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

      UniProtKB/TrEMBL
      Q5JPC5

    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
      UniProtKB/TrEMBL
      Q5JPC5

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

      UniProtKB/TrEMBL
      Q5JPC5

    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

      UniProtKB/TrEMBL
      Q5JPC5

    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

    Gene LinkOut

    The following LinkOut resources are supplied by external providers. These providers are responsible for maintaining the links.

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