Reactome | UniProt:Q8NB16 MLKL

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UniProt:Q8NB16 MLKL Show undefined attributes

chain	chain:1-471
checksum	005E7F7AB6D20649
comment	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).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).SUBUNIT Homooligomer (PubMed:29883610). Homotrimer; forms homotrimers on necroptosis induction (PubMed:24316671). Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3 (PubMed:22265414). Within this complex, may play a role in the proper targeting of RIPK1-RIPK3 to its downstream effector PGAM5 (PubMed:22265414). Interacts with RIPK3; the interaction is direct and promotes its phosphorylation and subsequent activation (PubMed:22265413, PubMed:22421439, PubMed:29883609).INTERACTION 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).ALTERNATIVE PRODUCTS The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys-230 and Gln-356 residues (By similarity). Upon phosphorylation by RIPK3, undergoes an active conformation (By similarity).DOMAIN The coiled coil region 2 is responsible for homotrimerization.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).MISCELLANEOUS Interaction with RIPK3 is species specific: human MLKL only interacts with human RIPK3 and not mouse RIPK3.SIMILARITY Belongs to the protein kinase superfamily.
created	[InstanceEdit:217385] Schmidt, EE, 2008-03-27 06:23:53
crossReference	[DatabaseIdentifier:12174196] PDB:4MWI [DatabaseIdentifier:12366064] RefSeq:NP_689862.1 [DatabaseIdentifier:12366063] RefSeq:XP_054235719.1 [DatabaseIdentifier:12366062] RefSeq:NP_001135969.1 [DatabaseIdentifier:12366065] RefSeq:XP_005255891.1 [DatabaseIdentifier:12285002] Pharos - Targets:Q8NB16 [DatabaseIdentifier:12263952] PRO:Q8NB16 [DatabaseIdentifier:12174197] PDB:8SLZ [DatabaseIdentifier:12174195] PDB:6D74 [DatabaseIdentifier:12174199] PDB:6BWK [DatabaseIdentifier:12174201] PDB:6ZPR [DatabaseIdentifier:11471402] ENSEMBL:ENSG00000168404 [DatabaseIdentifier:11568654] ENSEMBL:ENSP00000303118 [DatabaseIdentifier:11568655] ENSEMBL:ENSP00000308351 [DatabaseIdentifier:11691353] ENSEMBL:ENST00000306247 [DatabaseIdentifier:11691354] ENSEMBL:ENST00000308807 [DatabaseIdentifier:11780561] Guide to Pharmacology - Targets:2106 [DatabaseIdentifier:11787083] GeneCards:MLKL [DatabaseIdentifier:11802534] GlyGen:Q8NB16 [DatabaseIdentifier:11831020] HMDB Protein:HMDBP09462 [DatabaseIdentifier:11840159] HPA:ENSG00000168404-MLKL [DatabaseIdentifier:12124692] OpenTargets:ENSG00000168404 [DatabaseIdentifier:12174183] PDB:6ZZ1 [DatabaseIdentifier:12174191] PDB:2MSV [DatabaseIdentifier:12174186] PDB:7NM4 [DatabaseIdentifier:12174187] PDB:7NM5 [DatabaseIdentifier:12174192] PDB:7JW7 [DatabaseIdentifier:12174193] PDB:7JXU [DatabaseIdentifier:12174184] PDB:6ZLE [DatabaseIdentifier:12174190] PDB:6O5Z [DatabaseIdentifier:12174188] PDB:6UX8 [DatabaseIdentifier:12174182] PDB:4M67 [DatabaseIdentifier:12174181] PDB:5KO1 [DatabaseIdentifier:12174189] PDB:7NM2 [DatabaseIdentifier:12174185] PDB:6ZVO [DatabaseIdentifier:12174194] PDB:5KNJ [DatabaseIdentifier:12174198] PDB:6LK6 [DatabaseIdentifier:12145102] PDB:7MON [DatabaseIdentifier:12174200] PDB:6LK5
databaseName	UniProt
dbId	237490
description	recommendedName: fullName evidence="16"Mixed lineage kinase domain-like protein shortName evidence="12"hMLKL
displayName	UniProt:Q8NB16 MLKL
geneName	MLKL
identifier	Q8NB16
isSequenceChanged	false
keyword	3D-structure Alternative splicing ATP-binding Cell membrane Coiled coil Cytoplasm Membrane Necrosis Nucleotide-binding Nucleus Phosphoprotein Proteomics identification Reference proteome
modified	[InstanceEdit:9926675] Weiser, Joel, 2024-11-03
moleculeType	Protein
name	MLKL
physicalEntity	[EntityWithAccessionedSequence:R-HSA-5218901] MLKL [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-5218903] p-T357,S358-MLKL [cytosol] - Homo sapiens [EntityWithAccessionedSequence:R-HSA-9793468] K63PolyUb-K50,p-T357,S358-MLKL [cytosol] - Homo sapiens
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:ensembl:ENSG00000168404] ENSEMBL:ENSG00000168404 MLKL [ReferenceDNASequence:12737793] UCSC:Q8NB16 MLKL [ReferenceDNASequence:11336454] BioGPS Gene:197259 MLKL [ReferenceDNASequence:11399263] COSMIC - genes:MLKL MLKL [ReferenceDNASequence:11412639] CTD Gene:197259 MLKL [ReferenceDNASequence:11436239] dbSNP Gene:197259 MLKL [ReferenceDNASequence:11818721] HGNC:26617 MLKL [ReferenceDNASequence:11877559] KEGG:hsa:197259 MLKL [ReferenceDNASequence:11966243] Monarch:197259 MLKL [ReferenceDNASequence:12050336] NCBI Gene:197259 MLKL [ReferenceDNASequence:12110066] OMIM:615153 MLKL
referenceTranscript	[ReferenceRNASequence:12547900] RefSeq:NM_152649.4 MLKL [ReferenceRNASequence:12547903] RefSeq:XM_054379744.1 MLKL [ReferenceRNASequence:12547902] RefSeq:XM_005255834.5 MLKL [ReferenceRNASequence:12547901] RefSeq:NM_001142497.3 MLKL
schemaClass	ReferenceGeneProduct
secondaryIdentifier	MLKL_HUMAN A6NCE4 Q8N6V0
sequenceLength	471
species	[Species:48887] Homo sapiens
stId	uniprot:Q8NB16
url	http://purl.uniprot.org/uniprot/Q8NB16

Referrals

(referenceEntity)	[EntityWithAccessionedSequence:R-HSA-5218901] MLKL [cytosol] [EntityWithAccessionedSequence:R-HSA-5218903] p-T357,S358-MLKL [cytosol] [EntityWithAccessionedSequence:R-HSA-9793468] K63PolyUb-K50,p-T357,S358-MLKL [cytosol]
(referenceSequence)	[ModifiedResidue:5218885] O-phospho-L-serine at 358 [ModifiedResidue:5218912] O-phospho-L-threonine at 357 [GroupModifiedResidue:9793491] ubiquitinylated lysine (K63polyUb [cytosol]) at 50
(interactor)	[UndirectedInteraction:11161173] UniProt:Q9Y572 <-> UniProt:Q8NB16 (IntAct) [UndirectedInteraction:11213747] UniProt:Q8NB16 <-> ChEBI:63770 (IntAct)