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Protein

Mixed lineage kinase domain-like protein

Gene

MLKL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -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 (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).5 Publications

Miscellaneous

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

Activity regulationi

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-86.2 Publications

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
  • identical protein binding Source: IntAct
  • JUN kinase kinase kinase activity Source: GO_Central
  • protein-containing complex binding Source: UniProtKB
  • protein kinase binding Source: Ensembl
  • protein serine/threonine kinase activity Source: GO_Central

GO - Biological processi

Keywordsi

Biological processNecrosis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

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

EuPathDBiHostDB:ENSG00000168404.12
HGNCiHGNC:26617 MLKL
MIMi615153 gene
neXtProtiNX_Q8NB16

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

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
GuidetoPHARMACOLOGYi2106

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 RIPK32 Publications1
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
ProteomicsDBi72718
72719 [Q8NB16-2]

PTM databases

iPTMnetiQ8NB16
PhosphoSitePlusiQ8NB16

Expressioni

Gene expression databases

BgeeiENSG00000168404 Expressed in 184 organ(s), highest expression level in blood
CleanExiHS_MLKL
ExpressionAtlasiQ8NB16 baseline and differential
GenevisibleiQ8NB16 HS

Interactioni

Subunit structurei

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 PGAM5.6 Publications

Binary interactionsi

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

GO - Molecular functioni

Protein-protein interaction databases

BioGridi128244, 16 interactors
DIPiDIP-41782N
IntActiQ8NB16, 15 interactors
MINTiQ8NB16
STRINGi9606.ENSP00000308351

Structurei

Secondary structure

1471
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ8NB16
SMRiQ8NB16
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

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

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 149N-terminal bundle and brace (NBB); mediates INSP6 binding1 PublicationAdd BLAST149

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

Keywords - Domaini

Coiled coil

Phylogenomic databases

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

Family and domain databases

Gene3Di1.20.930.20, 1 hit
InterProiView protein in InterPro
IPR036537 Adaptor_Cbl_N_dom_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

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

This entry has 2 described isoforms and 4 potential isoforms that are computationally mapped.Show allAlign All

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

Computationally mapped potential isoform sequencesi

There are 4 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
I3L2T9I3L2T9_HUMAN
Mixed lineage kinase domain-like pr...
MLKL
211Annotation score:
I3L4Z5I3L4Z5_HUMAN
Mixed lineage kinase domain-like pr...
MLKL
62Annotation score:
I3L4A6I3L4A6_HUMAN
Mixed lineage kinase domain-like pr...
MLKL
175Annotation score:
I3L2U3I3L2U3_HUMAN
Mixed lineage kinase domain-like pr...
MLKL
102Annotation score:

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04135052S → T1 PublicationCorresponds to variant dbSNP:rs34251827Ensembl.1
Natural variantiVAR_041351100D → E1 PublicationCorresponds to variant dbSNP:rs33987771Ensembl.1
Natural variantiVAR_041352132S → P1 PublicationCorresponds to variant dbSNP:rs35589326Ensembl.1
Natural variantiVAR_041353146R → Q1 PublicationCorresponds to variant dbSNP:rs34515646Ensembl.1
Natural variantiVAR_041354169M → L1 PublicationCorresponds to variant dbSNP:rs55929310Ensembl.1
Natural variantiVAR_041355291L → P in a gastric adenocarcinoma sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs1313508921Ensembl.1
Natural variantiVAR_041356364T → M1 PublicationCorresponds to variant dbSNP:rs34389205Ensembl.1
Natural variantiVAR_041357398F → I in a gastric adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_041358421R → H1 PublicationCorresponds to variant dbSNP:rs55987292Ensembl.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

Similar proteinsi

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[»]
5KNJX-ray2.88A/B191-471[»]
5KO1X-ray2.16A191-471[»]
6BWKX-ray2.79A190-471[»]
ProteinModelPortaliQ8NB16
SMRiQ8NB16
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi128244, 16 interactors
DIPiDIP-41782N
IntActiQ8NB16, 15 interactors
MINTiQ8NB16
STRINGi9606.ENSP00000308351

Chemistry databases

ChEMBLiCHEMBL1938217
GuidetoPHARMACOLOGYi2106

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
ProteomicsDBi72718
72719 [Q8NB16-2]

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
EuPathDBiHostDB:ENSG00000168404.12
GeneCardsiMLKL
HGNCiHGNC:26617 MLKL
MIMi615153 gene
neXtProtiNX_Q8NB16
OpenTargetsiENSG00000168404
PharmGKBiPA142671349
GenAtlasiSearch...

Phylogenomic databases

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

Enzyme and pathway databases

ReactomeiR-HSA-3295583 TRP channels
R-HSA-5213460 RIPK1-mediated regulated necrosis

Miscellaneous databases

ChiTaRSiMLKL human
GenomeRNAii197259
PROiPR:Q8NB16
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000168404 Expressed in 184 organ(s), highest expression level in blood
CleanExiHS_MLKL
ExpressionAtlasiQ8NB16 baseline and differential
GenevisibleiQ8NB16 HS

Family and domain databases

Gene3Di1.20.930.20, 1 hit
InterProiView protein in InterPro
IPR036537 Adaptor_Cbl_N_dom_sf
IPR011009 Kinase-like_dom_sf
IPR000719 Prot_kinase_dom
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
PfamiView protein in Pfam
PF07714 Pkinase_Tyr, 1 hit
SUPFAMiSSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS50011 PROTEIN_KINASE_DOM, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiMLKL_HUMAN
AccessioniPrimary (citable) accession number: Q8NB16
Secondary accession number(s): A6NCE4, Q8N6V0
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 5, 2006
Last sequence update: October 1, 2002
Last modified: November 7, 2018
This is version 147 of the entry and version 1 of the sequence. See 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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

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

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