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Protein

Mixed lineage kinase domain-like protein

Gene

MLKL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

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.4 Publications

Enzyme regulationi

Inhibited by necrosulfonamide, a specific inhibitor of necroptosis that targets Cys-86.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sitei86Target of necrosulfonamide inhibitor1
Binding sitei230ATPCurated1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi209 – 217ATPPROSITE-ProRule annotation9

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • protein complex binding Source: UniProtKB

GO - Biological processi

  • necroptotic process Source: UniProtKB
  • protein homotrimerization Source: UniProtKB
  • protein phosphorylation Source: InterPro
Complete GO annotation...

Keywords - Biological processi

Necrosis

Keywords - Ligandi

ATP-binding, Nucleotide-binding

Enzyme and pathway databases

BioCyciZFISH:ENSG00000168404-MONOMER.
ReactomeiR-HSA-3295583. TRP channels.
R-HSA-5213460. RIPK1-mediated regulated necrosis.

Protein family/group databases

TCDBi1.A.105.1.1. the mixed lineage kinase domain-like (mlkl) family.

Names & Taxonomyi

Protein namesi
Recommended name:
Mixed lineage kinase domain-like protein
Short name:
hMLKL
Gene namesi
Name:MLKLImported
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 16

Organism-specific databases

HGNCiHGNC:26617. MLKL.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • cytosol Source: Reactome
  • plasma membrane Source: UniProtKB
Complete GO annotation...

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi58L → G: Does not affect formation of homotrimers, while translocation to the plasma membrane on necroptosis induction is impaired; when associated with G-76. 1 Publication1
Mutagenesisi76I → G: Does not affect formation of homotrimers, while translocation to the plasma membrane on necroptosis induction is impaired; when associated with G-58. 1 Publication1
Mutagenesisi86C → S: Abolishes binding to necrosulfonamide inhibitor. 1 Publication1
Mutagenesisi162L → G: Impairs formation of homotrimers and translocation to the plasma membrane on necroptosis induction; when associated with G-165. 1 Publication1
Mutagenesisi165L → G: Impairs formation of homotrimers and translocation to the plasma membrane on necroptosis induction; when associated with G-162. 1 Publication1
Mutagenesisi230K → M: Abolishes ATP-binding. 1 Publication1
Mutagenesisi331K → N: Impairs ATP-binding. 1 Publication1
Mutagenesisi351E → K: Binds ATP with an enhanced affinity. 1 Publication1
Mutagenesisi357 – 358TS → ED: Mimics phosphorylation state; acts as a dominant-negative mutant that impairs necroptosis. 2
Mutagenesisi357T → A: No effect. Abolishes ability to mediate necroptosis; when associated with A-358. 1 Publication1
Mutagenesisi358S → A: No effect. Abolishes ability to mediate necroptosis; when associated with A-357. 1 Publication1

Organism-specific databases

DisGeNETi197259.
OpenTargetsiENSG00000168404.
PharmGKBiPA142671349.

Chemistry databases

ChEMBLiCHEMBL1938217.

Polymorphism and mutation databases

BioMutaiMLKL.
DMDMi74762545.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002482391 – 471Mixed lineage kinase domain-like proteinAdd BLAST471

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei125PhosphoserineCombined sources1
Modified residuei357Phosphothreonine; by RIPK31 Publication1
Modified residuei358Phosphoserine; by RIPK31 Publication1
Modified residuei360Phosphoserine; by RIPK3By similarity1

Post-translational modificationi

Phosphorylation by RIPK3 induces a conformational switch that is required for necroptosis. It also induces homotrimerization and localization to the plasma membrane.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ8NB16.
MaxQBiQ8NB16.
PaxDbiQ8NB16.
PeptideAtlasiQ8NB16.
PRIDEiQ8NB16.

PTM databases

iPTMnetiQ8NB16.
PhosphoSitePlusiQ8NB16.

Expressioni

Gene expression databases

BgeeiENSG00000168404.
CleanExiHS_MLKL.
ExpressionAtlasiQ8NB16. baseline and differential.
GenevisibleiQ8NB16. HS.

Organism-specific databases

HPAiHPA046756.

Interactioni

Subunit structurei

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 PGAM5.4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
RIPK3Q9Y57210EBI-1055040,EBI-298250

GO - Molecular functioni

  • protein complex binding Source: UniProtKB

Protein-protein interaction databases

BioGridi128244. 14 interactors.
DIPiDIP-41782N.
IntActiQ8NB16. 13 interactors.
MINTiMINT-1033261.
STRINGi9606.ENSP00000308351.

Structurei

Secondary structure

1471
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi4 – 19Combined sources16
Beta strandi22 – 24Combined sources3
Helixi25 – 45Combined sources21
Turni46 – 48Combined sources3
Helixi56 – 78Combined sources23
Helixi82 – 91Combined sources10
Beta strandi93 – 96Combined sources4
Helixi99 – 119Combined sources21
Turni128 – 132Combined sources5
Helixi133 – 150Combined sources18
Helixi198 – 201Combined sources4
Beta strandi207 – 211Combined sources5
Beta strandi213 – 222Combined sources10
Beta strandi225 – 232Combined sources8
Helixi240 – 256Combined sources17
Beta strandi265 – 271Combined sources7
Beta strandi274 – 276Combined sources3
Beta strandi278 – 284Combined sources7
Helixi291 – 297Combined sources7
Helixi303 – 322Combined sources20
Beta strandi323 – 325Combined sources3
Helixi334 – 336Combined sources3
Beta strandi337 – 339Combined sources3
Beta strandi345 – 347Combined sources3
Helixi373 – 376Combined sources4
Helixi379 – 383Combined sources5
Helixi391 – 407Combined sources17
Turni411 – 414Combined sources4
Helixi417 – 425Combined sources9
Helixi439 – 448Combined sources10
Helixi453 – 455Combined sources3
Helixi459 – 467Combined sources9

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MSVNMR-A1-154[»]
4M67X-ray1.90A179-471[»]
4MWIX-ray1.70A183-471[»]
ProteinModelPortaliQ8NB16.
SMRiQ8NB16.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini194 – 469Protein kinasePROSITE-ProRule annotationAdd BLAST276

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili55 – 84Sequence analysisAdd BLAST30
Coiled coili139 – 180Sequence analysisAdd BLAST42

Domaini

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).By similarity
The coiled coil region 2 is responsible for homotrimerization.1 Publication

Sequence similaritiesi

Belongs to the protein kinase superfamily.Curated
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00390000016453.
HOGENOMiHOG000113601.
HOVERGENiHBG056156.
InParanoidiQ8NB16.
KOiK08849.
OMAiYKGEYHR.
OrthoDBiEOG091G05XI.
PhylomeDBiQ8NB16.
TreeFamiTF328453.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 12 Publications (identifier: Q8NB16-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MENLKHIITL GQVIHKRCEE MKYCKKQCRR LGHRVLGLIK PLEMLQDQGK
60 70 80 90 100
RSVPSEKLTT AMNRFKAALE EANGEIEKFS NRSNICRFLT ASQDKILFKD
110 120 130 140 150
VNRKLSDVWK ELSLLLQVEQ RMPVSPISQG ASWAQEDQQD ADEDRRAFQM
160 170 180 190 200
LRRDNEKIEA SLRRLEINMK EIKETLRQYL PPKCMQEIPQ EQIKEIKKEQ
210 220 230 240 250
LSGSPWILLR ENEVSTLYKG EYHRAPVAIK VFKKLQAGSI AIVRQTFNKE
260 270 280 290 300
IKTMKKFESP NILRIFGICI DETVTPPQFS IVMEYCELGT LRELLDREKD
310 320 330 340 350
LTLGKRMVLV LGAARGLYRL HHSEAPELHG KIRSSNFLVT QGYQVKLAGF
360 370 380 390 400
ELRKTQTSMS LGTTREKTDR VKSTAYLSPQ ELEDVFYQYD VKSEIYSFGI
410 420 430 440 450
VLWEIATGDI PFQGCNSEKI RKLVAVKRQQ EPLGEDCPSE LREIIDECRA
460 470
HDPSVRPSVD EILKKLSTFS K
Length:471
Mass (Da):54,479
Last modified:October 1, 2002 - v1
Checksum:i005E7F7AB6D20649
GO
Isoform 21 Publication (identifier: Q8NB16-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     179-205: YLPPKCMQEIPQEQIKEIKKEQLSGSP → SLESSSGKSPLEISRFKVKNVKTGSAS
     206-413: Missing.

Note: No experimental confirmation available.Curated
Show »
Length:263
Mass (Da):30,279
Checksum:i183FD0023D8A1EC3
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04135052S → T.1 PublicationCorresponds to variant rs34251827dbSNPEnsembl.1
Natural variantiVAR_041351100D → E.1 PublicationCorresponds to variant rs33987771dbSNPEnsembl.1
Natural variantiVAR_041352132S → P.1 PublicationCorresponds to variant rs35589326dbSNPEnsembl.1
Natural variantiVAR_041353146R → Q.1 PublicationCorresponds to variant rs34515646dbSNPEnsembl.1
Natural variantiVAR_041354169M → L.1 PublicationCorresponds to variant rs55929310dbSNPEnsembl.1
Natural variantiVAR_041355291L → P in a gastric adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_041356364T → M.1 PublicationCorresponds to variant rs34389205dbSNPEnsembl.1
Natural variantiVAR_041357398F → I in a gastric adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_041358421R → H.1 PublicationCorresponds to variant rs55987292dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_052133179 – 205YLPPK…LSGSP → SLESSSGKSPLEISRFKVKN VKTGSAS in isoform 2. 1 PublicationAdd BLAST27
Alternative sequenceiVSP_052134206 – 413Missing in isoform 2. 1 PublicationAdd BLAST208

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK091708 mRNA. Translation: BAC03728.1.
AC109599 Genomic DNA. No translation available.
BC028141 mRNA. Translation: AAH28141.1.
CCDSiCCDS32487.1. [Q8NB16-1]
CCDS45528.1. [Q8NB16-2]
RefSeqiNP_001135969.1. NM_001142497.2. [Q8NB16-2]
NP_689862.1. NM_152649.3. [Q8NB16-1]
XP_005255891.1. XM_005255834.3. [Q8NB16-1]
UniGeneiHs.119878.

Genome annotation databases

EnsembliENST00000306247; ENSP00000303118; ENSG00000168404. [Q8NB16-2]
ENST00000308807; ENSP00000308351; ENSG00000168404. [Q8NB16-1]
GeneIDi197259.
KEGGihsa:197259.
UCSCiuc002fdb.3. human. [Q8NB16-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK091708 mRNA. Translation: BAC03728.1.
AC109599 Genomic DNA. No translation available.
BC028141 mRNA. Translation: AAH28141.1.
CCDSiCCDS32487.1. [Q8NB16-1]
CCDS45528.1. [Q8NB16-2]
RefSeqiNP_001135969.1. NM_001142497.2. [Q8NB16-2]
NP_689862.1. NM_152649.3. [Q8NB16-1]
XP_005255891.1. XM_005255834.3. [Q8NB16-1]
UniGeneiHs.119878.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2MSVNMR-A1-154[»]
4M67X-ray1.90A179-471[»]
4MWIX-ray1.70A183-471[»]
ProteinModelPortaliQ8NB16.
SMRiQ8NB16.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi128244. 14 interactors.
DIPiDIP-41782N.
IntActiQ8NB16. 13 interactors.
MINTiMINT-1033261.
STRINGi9606.ENSP00000308351.

Chemistry databases

ChEMBLiCHEMBL1938217.

Protein family/group databases

TCDBi1.A.105.1.1. the mixed lineage kinase domain-like (mlkl) family.

PTM databases

iPTMnetiQ8NB16.
PhosphoSitePlusiQ8NB16.

Polymorphism and mutation databases

BioMutaiMLKL.
DMDMi74762545.

Proteomic databases

EPDiQ8NB16.
MaxQBiQ8NB16.
PaxDbiQ8NB16.
PeptideAtlasiQ8NB16.
PRIDEiQ8NB16.

Protocols and materials databases

DNASUi197259.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000306247; ENSP00000303118; ENSG00000168404. [Q8NB16-2]
ENST00000308807; ENSP00000308351; ENSG00000168404. [Q8NB16-1]
GeneIDi197259.
KEGGihsa:197259.
UCSCiuc002fdb.3. human. [Q8NB16-1]

Organism-specific databases

CTDi197259.
DisGeNETi197259.
GeneCardsiMLKL.
HGNCiHGNC:26617. MLKL.
HPAiHPA046756.
MIMi615153. gene.
neXtProtiNX_Q8NB16.
OpenTargetsiENSG00000168404.
PharmGKBiPA142671349.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00390000016453.
HOGENOMiHOG000113601.
HOVERGENiHBG056156.
InParanoidiQ8NB16.
KOiK08849.
OMAiYKGEYHR.
OrthoDBiEOG091G05XI.
PhylomeDBiQ8NB16.
TreeFamiTF328453.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000168404-MONOMER.
ReactomeiR-HSA-3295583. TRP channels.
R-HSA-5213460. RIPK1-mediated regulated necrosis.

Miscellaneous databases

ChiTaRSiMLKL. human.
GenomeRNAii197259.
PROiQ8NB16.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000168404.
CleanExiHS_MLKL.
ExpressionAtlasiQ8NB16. baseline and differential.
GenevisibleiQ8NB16. HS.

Family and domain databases

InterProiIPR011009. Kinase-like_dom.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
[Graphical view]
PfamiPF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiMLKL_HUMAN
AccessioniPrimary (citable) accession number: Q8NB16
Secondary accession number(s): A6NCE4, Q8N6V0
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 5, 2006
Last sequence update: October 1, 2002
Last modified: November 2, 2016
This is version 128 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Miscellaneous

Interaction with RIPK3 is species specific: human MLKL only interacts with human RIPK3 and not mouse RIPK3.1 Publication

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 16
    Human chromosome 16: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  6. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
  7. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.