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Protein

Mixed lineage kinase domain-like protein

Gene

Mlkl

Organism
Mus musculus (Mouse)
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:23835476, PubMed:24012422, PubMed:24019532). Binds to highly phosphorylated inositol phosphates such as inositolhexakisphosphate (InsP6) which is essential for its necroptotic function (By similarity).By similarity3 Publications

Miscellaneous

In contrast to human protein, not inhibited by necrosulfonamide, because a Trp residue is present instead of a Cys in position 85.1 Publication
Interaction with RIPK3 is species specific: mouse MLKL only interacts with mouse RIPK3 and not human RIPK3.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei219ATP1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi198 – 206ATPPROSITE-ProRule annotation9

GO - Molecular functioni

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

GO - Biological processi

Keywordsi

Biological processNecrosis
LigandATP-binding, Nucleotide-binding

Enzyme and pathway databases

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

Names & Taxonomyi

Protein namesi
Recommended name:
Mixed lineage kinase domain-like protein
Gene namesi
Name:MlklImported
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 8

Organism-specific databases

MGIiMGI:1921818 Mlkl

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

Disruption phenotypei

No visible phenotype: mice are viable, fertile and do not developmental or homeostatic phenotype in the absence of overt stress. However, these mice are resistant to TNF-induced necroptosis.2 Publications

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi219K → M: Abolishes ATP-binding and induces necroptosis in absence of exogeous stimuli and independently of RIPK3. 1 Publication1
Mutagenesisi239E → M: Retains ATP-binding ability. 1 Publication1
Mutagenesisi280L → P: Impaired ability to induce necroptosis. 1 Publication1
Mutagenesisi343Q → M: Retains ATP-binding ability and induces necroptosis in absence of exogeous stimuli and independently of RIPK3. 1 Publication1
Mutagenesisi345S → D: Mimics phosphorylation state and induces necroptosis in absence of exogeous stimuli and independently of RIPK3.e. 1 Publication1
Mutagenesisi385F → I: No effect. 1 Publication1
Mutagenesisi404 – 405SK → AA: Impairs interaction with RIPK3. 1 Publication2
Mutagenesisi404S → A: Impairs interaction with RIPK3. 1 Publication1

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00002482401 – 472Mixed lineage kinase domain-like proteinAdd BLAST472

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei124PhosphoserineBy similarity1
Modified residuei345Phosphoserine; by RIPK32 Publications1
Modified residuei347Phosphoserine; by RIPK32 Publications1
Modified residuei349Phosphothreonine; by RIPK32 Publications1
Modified residuei352Phosphoserine; by RIPK31 Publication1

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.2 Publications

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ9D2Y4
PeptideAtlasiQ9D2Y4
PRIDEiQ9D2Y4

PTM databases

iPTMnetiQ9D2Y4
PhosphoSitePlusiQ9D2Y4

Expressioni

Tissue specificityi

Highly expressed in thymus, colon, intestine, liver, spleen and lung. Expressed at much lower level in skeletal muscle, heart and kidney. Not detected in brain.1 Publication

Gene expression databases

BgeeiENSMUSG00000012519 Expressed in 95 organ(s), highest expression level in intestine
CleanExiMM_MLKL
ExpressionAtlasiQ9D2Y4 baseline and differential
GenevisibleiQ9D2Y4 MM

Interactioni

Subunit structurei

Homooligomer (By similarity). Homotrimer; forms homotrimers on necroptosis induction. 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 (By similarity). Interacts with RIPK3; the interaction is direct.By similarity4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
Ripk3Q9QZL03EBI-5401970,EBI-2367423

GO - Molecular functioni

Protein-protein interaction databases

IntActiQ9D2Y4, 4 interactors
STRINGi10090.ENSMUSP00000113718

Structurei

Secondary structure

1472
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

ProteinModelPortaliQ9D2Y4
SMRiQ9D2Y4
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini192 – 456Protein kinasePROSITE-ProRule annotationAdd BLAST265

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 143N-terminal bundle and brace (NBB); mediates INSP6 bindingBy similarityAdd BLAST143

Coiled coil

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Coiled coili61 – 81Sequence analysisAdd BLAST21
Coiled coili138 – 229Sequence analysisAdd BLAST92

Domaini

The coiled coil region 2 is responsible for homotrimerization.By similarity
The protein kinase domain is catalytically inactive but contains an unusual pseudoactive site with an interaction between Lys-219 and Gln-343 residues. Upon phosphorylation by RIPK3, undergoes an active conformation (PubMed:24012422, PubMed:24095729).2 Publications

Sequence similaritiesi

Belongs to the protein kinase superfamily.Curated

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00390000016453
HOGENOMiHOG000113601
HOVERGENiHBG056156
InParanoidiQ9D2Y4
KOiK08849
OMAiWQQEDQQ
OrthoDBiEOG091G05XI
PhylomeDBiQ9D2Y4
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 1 potential isoform that is computationally mapped.Show allAlign All

Isoform 11 Publication (identifier: Q9D2Y4-1) [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
MDKLGQIIKL GQLIYEQCEK MKYCRKQCQR LGNRVHGLLQ PLQRLQAQGK
60 70 80 90 100
KNLPDDITAA LGRFDEVLKE ANQQIEKFSK KSHIWKFVSV GNDKILFHEV
110 120 130 140 150
NEKLRDVWEE LLLLLQVYHW NTVSDVSQPA SWQQEDRQDA EEDGNENMKV
160 170 180 190 200
ILMQLQISVE EINKTLKQCS LKPTQEIPQD LQIKEIPKEH LGPPWTKLKT
210 220 230 240 250
SKMSTIYRGE YHRSPVTIKV FNNPQAESVG IVRFTFNDEI KTMKKFDSPN
260 270 280 290 300
ILRIFGICID QTVKPPEFSI VMEYCELGTL RELLDREKDL TMSVRSLLVL
310 320 330 340 350
RAARGLYRLH HSETLHRNIS SSSFLVAGGY QVKLAGFELS KTQNSISRTA
360 370 380 390 400
KSTKAERSSS TIYVSPERLK NPFCLYDIKA EIYSFGIVLW EIATGKIPFE
410 420 430 440 450
GCDSKKIREL VAEDKKQEPV GQDCPELLRE IINECRAHEP SQRPSVDGRS
460 470
LSGRERILER LSAVEESTDK KV
Length:472
Mass (Da):54,317
Last modified:June 1, 2001 - v1
Checksum:i75E0E3E3DDB5DFB2
GO
Isoform 22 Publications (identifier: Q9D2Y4-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     449-456: Missing.

Show »
Length:464
Mass (Da):53,375
Checksum:iFD609287F89D21B2
GO

Computationally mapped potential isoform sequencesi

There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
D3YV42D3YV42_MOUSE
Mixed lineage kinase domain-like pr...
Mlkl
176Annotation score:

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_052132449 – 456Missing in isoform 2. 2 Publications8

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK018636 mRNA Translation: BAB31320.1
AK170260 mRNA Translation: BAE41668.1
BC023755 mRNA Translation: AAH23755.1
CCDSiCCDS52671.1 [Q9D2Y4-2]
CCDS80932.1 [Q9D2Y4-1]
RefSeqiNP_001297542.1, NM_001310613.1 [Q9D2Y4-1]
NP_083281.1, NM_029005.3 [Q9D2Y4-2]
XP_006531505.1, XM_006531442.2 [Q9D2Y4-1]
UniGeneiMm.207971

Genome annotation databases

EnsembliENSMUST00000056157; ENSMUSP00000055521; ENSMUSG00000012519 [Q9D2Y4-1]
ENSMUST00000120432; ENSMUSP00000113718; ENSMUSG00000012519 [Q9D2Y4-2]
GeneIDi74568
KEGGimmu:74568
UCSCiuc009nmd.1 mouse [Q9D2Y4-2]
uc009nme.1 mouse [Q9D2Y4-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK018636 mRNA Translation: BAB31320.1
AK170260 mRNA Translation: BAE41668.1
BC023755 mRNA Translation: AAH23755.1
CCDSiCCDS52671.1 [Q9D2Y4-2]
CCDS80932.1 [Q9D2Y4-1]
RefSeqiNP_001297542.1, NM_001310613.1 [Q9D2Y4-1]
NP_083281.1, NM_029005.3 [Q9D2Y4-2]
XP_006531505.1, XM_006531442.2 [Q9D2Y4-1]
UniGeneiMm.207971

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4BTFX-ray2.60A1-472[»]
4M68X-ray1.70A182-472[»]
4M69X-ray2.50B182-472[»]
ProteinModelPortaliQ9D2Y4
SMRiQ9D2Y4
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ9D2Y4, 4 interactors
STRINGi10090.ENSMUSP00000113718

PTM databases

iPTMnetiQ9D2Y4
PhosphoSitePlusiQ9D2Y4

Proteomic databases

PaxDbiQ9D2Y4
PeptideAtlasiQ9D2Y4
PRIDEiQ9D2Y4

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000056157; ENSMUSP00000055521; ENSMUSG00000012519 [Q9D2Y4-1]
ENSMUST00000120432; ENSMUSP00000113718; ENSMUSG00000012519 [Q9D2Y4-2]
GeneIDi74568
KEGGimmu:74568
UCSCiuc009nmd.1 mouse [Q9D2Y4-2]
uc009nme.1 mouse [Q9D2Y4-1]

Organism-specific databases

CTDi197259
MGIiMGI:1921818 Mlkl

Phylogenomic databases

eggNOGiKOG0192 Eukaryota
COG0515 LUCA
GeneTreeiENSGT00390000016453
HOGENOMiHOG000113601
HOVERGENiHBG056156
InParanoidiQ9D2Y4
KOiK08849
OMAiWQQEDQQ
OrthoDBiEOG091G05XI
PhylomeDBiQ9D2Y4
TreeFamiTF328453

Enzyme and pathway databases

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

Miscellaneous databases

PROiPR:Q9D2Y4
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000012519 Expressed in 95 organ(s), highest expression level in intestine
CleanExiMM_MLKL
ExpressionAtlasiQ9D2Y4 baseline and differential
GenevisibleiQ9D2Y4 MM

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_MOUSE
AccessioniPrimary (citable) accession number: Q9D2Y4
Secondary accession number(s): Q8CIJ5
Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 5, 2006
Last sequence update: June 1, 2001
Last modified: November 7, 2018
This is version 140 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  4. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
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