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

Summary

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

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_000016.10 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

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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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

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.
MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy.
Title: MLKL promotes hepatocarcinogenesis through inhibition of AMPK-mediated autophagy.
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.
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.
MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis.
Title: MLKL polymerization-induced lysosomal membrane permeabilization promotes necroptosis.
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.
Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
Title: Phosphorylation-dependent pseudokinase domain dimerization drives full-length MLKL oligomerization.
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.
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.
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 EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

GDB:434012 (e-PCR)
- UniSTS:157204

RH69740 (e-PCR)
- UniSTS:49958

RH119437 (e-PCR)
- UniSTS:132978

SHGC-67307 (e-PCR)
- UniSTS:89991

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)

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
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

NC_000016.10 Reference GRCh38.p14 Primary Assembly

Range

74671855..74700862 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

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
XM_047433704.1 → XP_047289660.1 mixed lineage kinase domain-like protein isoform X2
XM_047433710.1 → XP_047289666.1 mixed lineage kinase domain-like protein isoform X8
XM_047433707.1 → XP_047289663.1 mixed lineage kinase domain-like protein isoform X5
XM_047433705.1 → XP_047289661.1 mixed lineage kinase domain-like protein isoform X3
XM_047433708.1 → XP_047289664.1 mixed lineage kinase domain-like protein isoform X6
XM_047433709.1 → XP_047289665.1 mixed lineage kinase domain-like protein isoform X7
XM_047433706.1 → XP_047289662.1 mixed lineage kinase domain-like protein isoform X4
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

NC_060940.1 Alternate T2T-CHM13v2.0

Range

80718597..80747927 complement

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

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

UniProtKB/Swiss-Prot

A6NCE4, Q8N6V0, Q8NB16
XM_054379745.1 → XP_054235720.1 mixed lineage kinase domain-like protein isoform X2
XM_054379752.1 → XP_054235727.1 mixed lineage kinase domain-like protein isoform X8
XM_054379748.1 → XP_054235723.1 mixed lineage kinase domain-like protein isoform X5
XM_054379746.1 → XP_054235721.1 mixed lineage kinase domain-like protein isoform X3
XM_054379749.1 → XP_054235724.1 mixed lineage kinase domain-like protein isoform X6
XM_054379750.1 → XP_054235725.1 mixed lineage kinase domain-like protein isoform X7
XM_054379747.1 → XP_054235722.1 mixed lineage kinase domain-like protein isoform X4
XM_054379751.1 → XP_054235726.1 mixed lineage kinase domain-like protein isoform X7