MLKL
entrez
197259
canonical
uniprot
Q8NB16
canonical
ensembl
ENSG00000168404
resolver
ensp
ENSP00000303118
resolver
ensp
ENSP00000308351
resolver
ensp
ENSP00000532212
resolver
ensp
ENSP00000669895
resolver
ensp
ENSP00000669896
resolver
ensp
ENSP00000669898
resolver
ensp
ENSP00000727335
resolver
ensp
ENSP00000727337
resolver
genesymbol
MLKL
resolver
hgnc
HGNC:26617
resolver
uniprot
A6NCE4
resolver
uniprot
Q8N6V0
resolver
uniprot_entry
MLKL_HUMAN
resolver
uniprot_sec
A6NCE4
resolver
uniprot_sec
Q8N6V0
resolver
activity_regulation
ACTIVITY REGULATION: Activated via binding to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which mediates the release of an N-terminal auto-inhibitory region (PubMed:29883610). 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 (PubMed:22265413). {ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:29883610}.
uniprot
proteins
amino_acid_sequence
MENLKHIITLGQVIHKRCEEMKYCKKQCRRLGHRVLGLIKPLEMLQDQGKRSVPSEKLTTAMNRFKAALEEANGEIEKFSNRSNICRFLTASQDKILFKDVNRKLSDVWKELSLLLQVEQRMPVSPISQGASWAQEDQQDADEDRRAFQMLRRDNEKIEASLRRLEINMKEIKETLRQYLPPKCMQEIPQEQIKEIKKEQLSGSPWILLRENEVSTLYKGEYHRAPVAIKVFKKLQAGSIAIVRQTFNKEIKTMKKFESPNILRIFGICIDETVTPPQFSIVMEYCELGTLRELLDREKDLTLGKRMVLVLGAARGLYRLHHSEAPELHGKIRSSNFLVTQGYQVKLAGFELRKTQTSMSLGTTREKTDRVKSTAYLSPQELEDVFYQYDVKSEIYSFGIVLWEIATGDIPFQGCNSEKIRKLVAVKRQQEPLGEDCPSELREIIDECRAHDPSVRPSVDEILKKLSTFSK
uniprot
proteins
function
FUNCTION: Pseudokinase that plays a key role in TNF-induced necroptosis, a programmed cell death process (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). Does not have protein kinase activity (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). 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 (PubMed:22265413, PubMed:22265414, PubMed:22421439, PubMed:24316671). In addition to TNF-induced necroptosis, necroptosis can also take place in the nucleus in response to orthomyxoviruses infection: following activation by ZBP1, MLKL is phosphorylated by RIPK3 in the nucleus, triggering disruption of the nuclear envelope and leakage of cellular DNA into the cytosol.following ZBP1 activation, which senses double-stranded Z-RNA structures, nuclear RIPK3 catalyzes phosphorylation and activation of MLKL, promoting disruption of the nuclear envelope and leakage of cellular DNA into the cytosol (By similarity). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (PubMed:29883610). {ECO:0000250|UniProtKB:Q9D2Y4, ECO:0000269|PubMed:22265413, ECO:0000269|PubMed:22265414, ECO:0000269|PubMed:22421439, ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}.
uniprot
proteins
mass_dalton
54479
uniprot
proteins
mutagenesis
MUTAGEN 58; /note="L->G: Does not affect formation of homotrimers, while translocation to the plasma membrane on necroptosis induction is impaired; when associated with G-76."; /evidence="ECO:0000269|PubMed:24316671"; MUTAGEN 76; /note="I->G: Does not affect formation of homotrimers, while translocation to the plasma membrane on necroptosis induction is impaired; when associated with G-58."; /evidence="ECO:0000269|PubMed:24316671"; MUTAGEN 86; /note="C->S: Abolishes binding to necrosulfonamide inhibitor."; /evidence="ECO:0000269|PubMed:22265413"; MUTAGEN 162; /note="L->G: Impairs formation of homotrimers and translocation to the plasma membrane on necroptosis induction; when associated with G-165."; /evidence="ECO:0000269|PubMed:24316671"; MUTAGEN 165; /note="L->G: Impairs formation of homotrimers and translocation to the plasma membrane on necroptosis induction; when associated with G-162."; /evidence="ECO:0000269|PubMed:24316671"; MUTAGEN 230; /note="K->M: Abolishes ATP-binding."; /evidence="ECO:0000269|PubMed:24219132"; MUTAGEN 331; /note="K->N: Impairs ATP-binding."; /evidence="ECO:0000269|PubMed:24219132"; MUTAGEN 351; /note="E->K: Binds ATP with an enhanced affinity."; /evidence="ECO:0000269|PubMed:24219132"; MUTAGEN 357..358; /note="TS->ED: Mimics phosphorylation state; acts as a dominant-negative mutant that impairs necroptosis."; MUTAGEN 357; /note="T->A: No effect. Abolishes ability to mediate necroptosis; when associated with A-358."; /evidence="ECO:0000269|PubMed:22265413"; MUTAGEN 358; /note="S->A: No effect. Abolishes ability to mediate necroptosis; when associated with A-357."; /evidence="ECO:0000269|PubMed:22265413
uniprot
proteins
post_translational_modification
PTM: Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis (PubMed:22265413). It also induces homotrimerization and localization to the plasma membrane (PubMed:22265413). {ECO:0000269|PubMed:22265413}.
uniprot
proteins
protein_family
Protein kinase superfamily
uniprot
proteins
pubmed
12471243
uniprot
proteins
pubmed
14702039
uniprot
proteins
pubmed
15489334
uniprot
proteins
pubmed
15616553
uniprot
proteins
pubmed
17344846
uniprot
proteins
pubmed
18669648
uniprot
proteins
pubmed
18691976
uniprot
proteins
pubmed
19690332
uniprot
proteins
pubmed
20068231
uniprot
proteins
pubmed
21269460
uniprot
proteins
pubmed
22265413
uniprot
proteins
pubmed
22265414
uniprot
proteins
pubmed
22421439
uniprot
proteins
pubmed
24095729
uniprot
proteins
pubmed
24219132
uniprot
proteins
pubmed
24316671
uniprot
proteins
pubmed
29883609
uniprot
proteins
pubmed
29883610
uniprot
proteins
sequence_length
471
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:24316671}. Cell membrane {ECO:0000269|PubMed:24316671, ECO:0000269|PubMed:29883610}. Nucleus {ECO:0000250|UniProtKB:Q9D2Y4}. Note=Localizes to the cytoplasm and translocates to the plasma membrane on necroptosis induction (PubMed:24316671). Localizes to the nucleus in response to orthomyxoviruses infection (By similarity). {ECO:0000250|UniProtKB:Q9D2Y4, ECO:0000269|PubMed:24316671}.
uniprot
proteins