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 (RIP... See more...

Aliases for MLKL Gene

Aliases for MLKL Gene

  • Mixed Lineage Kinase Domain Like Pseudokinase 2 3 5
  • Mixed Lineage Kinase Domain-Like Protein 3 4
  • HMLKL 3 4
  • Mixed Lineage Kinase Domain-Like 2
  • FLJ34389 2
  • MLKL 5

External Ids for MLKL Gene

Previous GeneCards Identifiers for MLKL Gene

  • GC16M073264
  • GC16M074705
  • GC16M060455

Summaries for MLKL Gene

Entrez Gene Summary for MLKL Gene

  • 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]

GeneCards Summary for MLKL Gene

MLKL (Mixed Lineage Kinase Domain Like Pseudokinase) is a Protein Coding gene. Diseases associated with MLKL include Caspase 8 Deficiency and Inflammatory Bowel Disease. Among its related pathways are Necroptosis and DNA Damage Response (only ATM dependent). Gene Ontology (GO) annotations related to this gene include transferase activity, transferring phosphorus-containing groups and protein tyrosine kinase activity. An important paralog of this gene is BRAF.

UniProtKB/Swiss-Prot Summary for MLKL Gene

  • Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process. Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage. Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610).

No data available for CIViC Summary , Tocris Summary , Gene Wiki entry , PharmGKB "VIP" Summary , Rfam classification and piRNA Summary for MLKL Gene

Genomics for MLKL Gene

GeneHancer (GH) Regulatory Elements Pubs

Promoters and enhancers for MLKL Gene
- Elite GeneHancer and/or Elite GeneHancer-gene association Download GeneHancer data from 2017 publication | Request up-to-date GeneHancer data (full dataset)

GeneHancers around MLKL on the GeneHancer Hub at the UCSC Golden Path

Cistromic (ChIP-Seq) regulation report from SPP (The Signaling Pathways Project) for MLKL

Top Transcription factor binding sites by QIAGEN in the MLKL gene promoter:
  • AML1a
  • C/EBPalpha
  • CREB
  • deltaCREB
  • E4BP4
  • En-1
  • Evi-1
  • NRF-2
  • POU6F1 (c2)
  • TBP

Genomic Locations for MLKL Gene

Genomic Locations for MLKL Gene
chr16:74,671,855-74,700,960
(GRCh38/hg38)
Size:
29,106 bases
Orientation:
Minus strand
chr16:74,705,753-74,734,858
(GRCh37/hg19)
Size:
29,106 bases
Orientation:
Minus strand

Genomic View for MLKL Gene

Genes around MLKL on UCSC Golden Path with GeneCards custom track

Cytogenetic band:
MLKL Gene in genomic location: bands according to Ensembl, locations according to GeneLoc (and/or Entrez Gene and/or Ensembl if different)
Genomic Location for MLKL Gene
GeneLoc Logo Genomic Neighborhood Exon StructureGene Density

RefSeq DNA sequence for MLKL Gene

Proteins for MLKL Gene

  • Protein details for MLKL Gene (UniProtKB/Swiss-Prot)

    Protein Symbol:
    Q8NB16-MLKL_HUMAN
    Recommended name:
    Mixed lineage kinase domain-like protein
    Protein Accession:
    Q8NB16
    Secondary Accessions:
    • A6NCE4
    • Q8N6V0

    Protein attributes for MLKL Gene

    Size:
    471 amino acids
    Molecular mass:
    54479 Da
    Quaternary structure:
    • Homooligomer (PubMed:29883610). Homotrimer; forms homotrimers on necroptosis induction. Interacts with RIPK3; the interaction is direct. Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3. Within this complex, may play a role in the proper targeting of RIPK1/RIPK3 to its downstream effector PGAM5.
    Miscellaneous:
    • Interaction with RIPK3 is species specific: human MLKL only interacts with human RIPK3 and not mouse RIPK3.

    Three dimensional structures from OCA and Proteopedia for MLKL Gene

    Alternative splice isoforms for MLKL Gene

    UniProtKB/Swiss-Prot:

neXtProt entry for MLKL Gene

Post-translational modifications for MLKL Gene

  • Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis. It also induces homotrimerization and localization to the plasma membrane.
  • Modification sites at PhosphoSitePlus
  • Modification sites at neXtProt

No data available for DME Specific Peptides for MLKL Gene

Domains & Families for MLKL Gene

Gene Families for MLKL Gene

IUPHAR :
Human Protein Atlas (HPA):
  • Enzymes
  • Predicted intracellular proteins
  • Transporters

Suggested Antigen Peptide Sequences for MLKL Gene

GenScript: Design optimal peptide antigens:
  • Mixed lineage kinase domain-like protein (MLKL_HUMAN)

Graphical View of Domain Structure for InterPro Entry

Q8NB16

UniProtKB/Swiss-Prot:

MLKL_HUMAN :
  • The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys-230 and Gln-356 residues. Upon phosphorylation by RIPK3, undergoes an active conformation (By similarity).
  • Belongs to the protein kinase superfamily.
Domain:
  • The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys-230 and Gln-356 residues. Upon phosphorylation by RIPK3, undergoes an active conformation (By similarity).
  • The coiled coil region 2 is responsible for homotrimerization.
Family:
  • Belongs to the protein kinase superfamily.
genes like me logo Genes that share domains with MLKL: view

Function for MLKL Gene

Molecular function for MLKL Gene

UniProtKB/Swiss-Prot Function:
Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process. Activated following phosphorylation by RIPK3, leading to homotrimerization, localization to the plasma membrane and execution of programmed necrosis characterized by calcium influx and plasma membrane damage. Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610).
UniProtKB/Swiss-Prot EnzymeRegulation:
Activated via binding to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which mediates the release of an N-terminal auto-inhibitory region. Activation requires not only RIPK3-dependent phosphorylation but also binding to highly phosphorylated inositol phosphates (PubMed:29883610). Inhibited by necrosulfonamide, a specific inhibitor of necroptosis that targets Cys-86.

Phenotypes From GWAS Catalog for MLKL Gene

Gene Ontology (GO) - Molecular Function for MLKL Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0000166 nucleotide binding IEA --
GO:0004672 NOT protein kinase activity IEA,ISS --
GO:0004706 JUN kinase kinase kinase activity IBA 21873635
GO:0005515 protein binding IPI 22265413
GO:0005524 ATP binding IEA,IDA 24219132
genes like me logo Genes that share ontologies with MLKL: view
genes like me logo Genes that share phenotypes with MLKL: view

Animal Models for MLKL Gene

MGI Knock Outs for MLKL:
  • Mlkl Mlkl<tm1.2Wsa>

Animal Model Products

  • Taconic Biosciences Mouse Models for MLKL

CRISPR Products

Inhibitory RNA Products

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for MLKL

No data available for Enzyme Numbers (IUBMB) , Human Phenotype Ontology , miRNA , Transcription Factor Targets and HOMER Transcription for MLKL Gene

Localization for MLKL Gene

Subcellular locations from UniProtKB/Swiss-Prot for MLKL Gene

Cytoplasm. Cell membrane. Note=Localizes to the cytoplasm and translocates to the plasma membrane on necroptosis induction.

Subcellular locations from

COMPARTMENTS
Extracellular space Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi Apparatus Nucleus Mitochondrion 0 1 2 3 4 5 Confidence
COMPARTMENTS Subcellular localization image for MLKL gene
Compartment Confidence
plasma membrane 5
cytosol 5
nucleus 4
mitochondrion 3
extracellular 2
cytoskeleton 2
endoplasmic reticulum 2
endosome 2
lysosome 2
peroxisome 1
golgi apparatus 1

Gene Ontology (GO) - Cellular Components for MLKL Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0005737 cytoplasm IEA,IDA 24316671
GO:0005829 cytosol TAS --
GO:0005886 plasma membrane IEA,IDA 24316671
GO:0016020 membrane IEA --
genes like me logo Genes that share ontologies with MLKL: view

No data available for Subcellular locations from the Human Protein Atlas (HPA) for MLKL Gene

Pathways & Interactions for MLKL Gene

genes like me logo Genes that share pathways with MLKL: view

Pathways by source for MLKL Gene

1 Cell Signaling Technology pathway for MLKL Gene

Gene Ontology (GO) - Biological Process for MLKL Gene

GO ID Qualified GO term Evidence PubMed IDs
GO:0006468 protein phosphorylation IEA --
GO:0007166 cell surface receptor signaling pathway IEA --
GO:0007257 activation of JUN kinase activity IBA 21873635
GO:0012501 programmed cell death IEA --
GO:0070207 protein homotrimerization IDA 24316671
genes like me logo Genes that share ontologies with MLKL: view

No data available for SIGNOR curated interactions for MLKL Gene

Drugs & Compounds for MLKL Gene

(1) Drugs for MLKL Gene - From: HMDB

Name Status Disease Links Group Role Mechanism of Action Clinical Trials
ATP Investigational Nutra Agonist, Activator, Partial agonist, Antagonist, Full agonist, Gating inhibitor, Pore Blocker, Potentiation 0

(1) Additional Compounds for MLKL Gene - From: HMDB

Name Synonyms Role CAS Number PubChem IDs PubMed IDs
ADP
  • 5'-Adenylphosphoric acid
  • Adenosine 5'-diphosphate
  • ADENOSINE-5'-diphosphATE
  • H3ADP
  • 5'-Adenylphosphate
Agonist, Full agonist, Partial agonist, Gating inhibitor, Antagonist 58-64-0
genes like me logo Genes that share compounds with MLKL: view

Transcripts for MLKL Gene

mRNA/cDNA for MLKL Gene

2 REFSEQ mRNAs :
8 NCBI additional mRNA sequence :
8 Ensembl transcripts including schematic representations, and UCSC links to gene/alias where relevant :

CRISPR Products

Inhibitory RNA Products

  • Search GeneCopoeia for shRNA, lentivirus and/or AAV clone products for MLKL

Alternative Splicing Database (ASD) splice patterns (SP) for MLKL Gene

ExUns: 1 ^ 2 ^ 3 ^ 4 ^ 5 ^ 6 ^ 7a · 7b ^ 8a · 8b ^ 9a · 9b ^ 10 ^ 11
SP1: - - -
SP2: -
SP3: - - - - - - - -
SP4:

Relevant External Links for MLKL Gene

GeneLoc Exon Structure for
MLKL

Expression for MLKL Gene

mRNA expression in normal human tissues from GTEx, Illumina, BioGPS, and SAGE for MLKL Gene

mRNA expression in embryonic tissues and stem cells from LifeMap Discovery

mRNA differential expression in normal tissues according to GTEx for MLKL Gene

This gene is overexpressed in Whole Blood (x10.1).

Protein differential expression in normal tissues from HIPED for MLKL Gene

This gene is overexpressed in Peripheral blood mononuclear cells (14.8) and Lymph node (10.3).

Integrated Proteomics: protein expression in normal tissues and cell lines from ProteomicsDB, MaxQB, and MOPED for MLKL Gene



Protein tissue co-expression partners for MLKL Gene

- Elite partner

Transcriptomic regulation report from SPP (The Signaling Pathways Project) for MLKL

SOURCE GeneReport for Unigene cluster for MLKL Gene:

Hs.119878

Evidence on tissue expression from TISSUES for MLKL Gene

  • Intestine(2.9)
  • Kidney(2.8)
  • Spleen(2.7)
  • Blood(2.7)
  • Heart(2.7)
  • Bone marrow(2.6)
  • Liver(2.5)
  • Lymph node(2.5)
  • Lung(2.4)
  • Nervous system(2.4)
  • Skin(2.4)
  • Muscle(2.2)
  • Thyroid gland(2.2)
genes like me logo Genes that share expression patterns with MLKL: view

No data available for mRNA Expression by UniProt/SwissProt and Phenotype-based relationships between genes and organs from Gene ORGANizer for MLKL Gene

Orthologs for MLKL Gene

This gene was present in the common ancestor of chordates.

Orthologs for MLKL Gene

Organism Taxonomy Gene Similarity Type Details
Chimpanzee
(Pan troglodytes)
Mammalia MLKL 30 31
  • 98.8 (n)
OneToOne
Cow
(Bos Taurus)
Mammalia MLKL 30 31
  • 77.47 (n)
OneToOne
Mouse
(Mus musculus)
Mammalia Mlkl 30 17 31
  • 75.92 (n)
OneToOne
Rat
(Rattus norvegicus)
Mammalia Mlkl 30
  • 75.81 (n)
Platypus
(Ornithorhynchus anatinus)
Mammalia MLKL 31
  • 48 (a)
OneToOne
Chicken
(Gallus gallus)
Aves MLKL 30 31
  • 54.2 (n)
OneToOne
Lizard
(Anolis carolinensis)
Reptilia MLKL 31
  • 41 (a)
OneToOne
Tropical Clawed Frog
(Silurana tropicalis)
Amphibia mlkl 30
  • 48.97 (n)
Sea Squirt
(Ciona savignyi)
Ascidiacea -- 31
  • 24 (a)
OneToOne
Species where no ortholog for MLKL was found in the sources mined by GeneCards:
  • A. gosspyii yeast (Eremothecium gossypii)
  • Actinobacteria (Mycobacterium tuberculosis)
  • African clawed frog (Xenopus laevis)
  • African malaria mosquito (Anopheles gambiae)
  • Alicante grape (Vitis vinifera)
  • Alpha proteobacteria (Wolbachia pipientis)
  • Amoeba (Dictyostelium discoideum)
  • Archea (Pyrococcus horikoshii)
  • Baker's yeast (Saccharomyces cerevisiae)
  • Barley (Hordeum vulgare)
  • Beta proteobacteria (Neisseria meningitidis)
  • Bread mold (Neurospora crassa)
  • Chromalveolata (Phytophthora infestans)
  • Common water flea (Daphnia pulex)
  • Corn (Zea mays)
  • Dog (Canis familiaris)
  • E. coli (Escherichia coli)
  • Filamentous fungi (Aspergillus nidulans)
  • Firmicute Bacteria (Streptococcus pneumoniae)
  • Fission Yeast (Schizosaccharomyces pombe)
  • Fruit Fly (Drosophila melanogaster)
  • Green Algae (Chlamydomonas reinhardtii)
  • Honey Bee (Apis mellifera)
  • K. Lactis Yeast (Kluyveromyces lactis)
  • Loblloly Pine (Pinus taeda)
  • Malaria Parasite (Plasmodium falciparum)
  • Medicago Trunc (Medicago Truncatula)
  • Moss (Physcomitrella patens)
  • Oppossum (Monodelphis domestica)
  • Orangutan (Pongo pygmaeus)
  • Pig (Sus scrofa)
  • Rainbow Trout (Oncorhynchus mykiss)
  • Rice (Oryza sativa)
  • Rice Blast Fungus (Magnaporthe grisea)
  • Schistosome Parasite (Schistosoma mansoni)
  • Sea Anemone (Nematostella vectensis)
  • Sea Vase (Ciona intestinalis)
  • Sea Urchin (Strongylocentrotus purpuratus)
  • Sorghum (Sorghum bicolor)
  • Soybean (Glycine max)
  • Stem Rust Fungus (Puccinia graminis)
  • Sugarcane (Saccharum officinarum)
  • Thale Cress (Arabidopsis thaliana)
  • Tomato (Lycopersicon esculentum)
  • Toxoplasmosis (Toxoplasma gondii)
  • Trichoplax (Trichoplax adhaerens)
  • Wheat (Triticum aestivum)
  • Worm (Caenorhabditis elegans)
  • Zebrafish (Danio rerio)

Evolution for MLKL Gene

ENSEMBL:
Gene Tree for MLKL (if available)
TreeFam:
Gene Tree for MLKL (if available)
Aminode:
Evolutionary constrained regions (ECRs) for MLKL: view image

Paralogs for MLKL Gene

(2) SIMAP similar genes for MLKL Gene using alignment to 5 proteins:

  • MLKL_HUMAN
  • I3L2T9_HUMAN
  • I3L2U3_HUMAN
  • I3L4A6_HUMAN
  • I3L4Z5_HUMAN
genes like me logo Genes that share paralogs with MLKL: view

Variants for MLKL Gene

Sequence variations, with clinical significance, from ClinVar and Humsavar, with links to dbSNP for MLKL Gene

SNP ID Clinical significance and condition Chr 16 pos Variation AA Info Type
716578 Benign: not provided 74,691,297(-) T/C SYNONYMOUS_VARIANT,INTRON_VARIANT
770791 Benign: not provided 74,695,757(-) T/C INITIATIOR_CODON_VARIANT,MISSENSE_VARIANT
788368 Benign: not provided 74,695,458(-) G/C MISSENSE_VARIANT
791336 Benign: not provided 74,682,727(-) G/A SYNONYMOUS_VARIANT,INTRON_VARIANT
rs1313508921 A gastric adenocarcinoma sample p.Leu291Pro

Additional dbSNP identifiers (rs#s) for MLKL Gene

Structural Variations from Database of Genomic Variants (DGV) for MLKL Gene

Variant ID Type Subtype PubMed ID
esv275138 CNV gain+loss 21479260
esv2760414 CNV gain 21179565

Variation tolerance for MLKL Gene

Residual Variation Intolerance Score: 93.9% of all genes are more intolerant (likely to be disease-causing)
Gene Damage Index Score: 2.08; 38.02% of all genes are more intolerant (likely to be disease-causing)

Additional Variant Information for MLKL Gene

SNPedia medical, phenotypic, and genealogical associations of SNPs for
MLKL

SNP Genotyping and Copy Number Assay Products

No data available for Polymorphic Variants from UniProtKB/Swiss-Prot for MLKL Gene

Disorders for MLKL Gene

MalaCards: The human disease database

(6) MalaCards diseases for MLKL Gene - From: DISEASES and GeneCards

Disorder Aliases PubMed IDs
caspase 8 deficiency
  • ceds
inflammatory bowel disease
  • inflammatory bowel diseases
maxillary sinus inverted papilloma
  • inverted papilloma of the maxillary sinus
cecal disease
  • disorder of cecum
autoimmune lymphoproliferative syndrome
  • css
- elite association - COSMIC cancer census association via MalaCards
Search MLKL in MalaCards View complete list of genes associated with diseases

Additional Disease Information for MLKL

Genetic Association Database
(GAD)
Human Genome Epidemiology Navigator
(HuGE)
ATLAS of Genetics and Cytogenetics in Oncology and Haematology
Open Targets Platform
genes like me logo Genes that share disorders with MLKL: view

No data available for UniProtKB/Swiss-Prot and Genatlas for MLKL Gene

Publications for MLKL Gene

  1. PELI1 Selectively Targets Kinase-Active RIP3 for Ubiquitylation-Dependent Proteasomal Degradation. (PMID: 29883609) Choi SW … Kim YS (Molecular cell 2018) 3 4
  2. MLKL Requires the Inositol Phosphate Code to Execute Necroptosis. (PMID: 29883610) Dovey CM … Carette JE (Molecular cell 2018) 3 4
  3. A tale of two domains - a structural perspective of the pseudokinase, MLKL. (PMID: 26337687) Czabotar PE … Murphy JM (The FEBS journal 2015) 2 3
  4. Insights into the evolution of divergent nucleotide-binding mechanisms among pseudokinases revealed by crystal structures of human and mouse MLKL. (PMID: 24219132) Murphy JM … Czabotar PE (The Biochemical journal 2014) 3 4
  5. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. (PMID: 24316671) Cai Z … Liu ZG (Nature cell biology 2014) 3 4

Products for MLKL Gene

Sources for MLKL Gene