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Protein

Mixed lineage kinase domain-like protein

Gene

Mlkl

Organism
Mus musculus (Mouse)
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.3 Publications

Sites

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Binding sitei219 – 2191ATP

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Nucleotide bindingi198 – 2069ATPPROSITE-ProRule annotation

GO - Molecular functioni

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

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 lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 8

Organism-specific databases

MGIiMGI:1921818. Mlkl.

Subcellular locationi

  • Cytoplasm By similarity
  • Cell membrane By similarity

  • Note: Localizes to the cytoplasm and translocates to the plasma membrane on necroptosis induction.By similarity

GO - Cellular componenti

Complete GO annotation...

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)LengthDescriptionGraphical viewFeature identifierActions
Mutagenesisi219 – 2191K → M: Abolishes ATP-binding and induces necroptosis in absence of exogeous stimuli and independently of RIPK3. 1 Publication
Mutagenesisi239 – 2391E → M: Retains ATP-binding ability. 1 Publication
Mutagenesisi280 – 2801L → P: Impaired ability to induce necroptosis. 1 Publication
Mutagenesisi343 – 3431Q → M: Retains ATP-binding ability and induces necroptosis in absence of exogeous stimuli and independently of RIPK3. 1 Publication
Mutagenesisi345 – 3451S → D: Mimics phosphorylation state and induces necroptosis in absence of exogeous stimuli and independently of RIPK3.e. 1 Publication
Mutagenesisi385 – 3851F → I: No effect. 1 Publication
Mutagenesisi404 – 4052SK → AA: Impairs interaction with RIPK3. 1 Publication
Mutagenesisi404 – 4041S → A: Impairs interaction with RIPK3. 1 Publication

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 472472Mixed lineage kinase domain-like proteinPRO_0000248240Add
BLAST

Amino acid modifications

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Modified residuei124 – 1241PhosphoserineBy similarity
Modified residuei345 – 3451Phosphoserine; by RIPK32 Publications
Modified residuei347 – 3471Phosphoserine; by RIPK32 Publications
Modified residuei349 – 3491Phosphothreonine; by RIPK32 Publications
Modified residuei352 – 3521Phosphoserine; by RIPK31 Publication

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

MaxQBiQ9D2Y4.
PaxDbiQ9D2Y4.
PeptideAtlasiQ9D2Y4.
PRIDEiQ9D2Y4.

PTM databases

iPTMnetiQ9D2Y4.
PhosphoSiteiQ9D2Y4.

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.
CleanExiMM_MLKL.
ExpressionAtlasiQ9D2Y4. baseline and differential.
GenevisibleiQ9D2Y4. MM.

Interactioni

Subunit structurei

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

GO - Molecular functioni

  • protein complex binding Source: MGI
  • protein kinase binding Source: UniProtKB

Protein-protein interaction databases

IntActiQ9D2Y4. 2 interactions.
STRINGi10090.ENSMUSP00000113718.

Structurei

Secondary structure

1
472
Legend: HelixTurnBeta strand
Show more details
Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Helixi3 – 1816Combined sources
Beta strandi22 – 243Combined sources
Helixi25 – 4723Combined sources
Helixi55 – 7723Combined sources
Helixi98 – 11417Combined sources
Helixi132 – 15423Combined sources
Helixi159 – 16810Combined sources
Helixi188 – 1903Combined sources
Beta strandi196 – 2005Combined sources
Beta strandi202 – 21110Combined sources
Beta strandi214 – 22310Combined sources
Helixi229 – 24214Combined sources
Beta strandi254 – 2607Combined sources
Beta strandi263 – 2653Combined sources
Beta strandi267 – 2737Combined sources
Helixi280 – 2867Combined sources
Helixi292 – 31120Combined sources
Turni321 – 3233Combined sources
Beta strandi324 – 3274Combined sources
Helixi328 – 3303Combined sources
Beta strandi331 – 3344Combined sources
Beta strandi336 – 3394Combined sources
Helixi340 – 3478Combined sources
Helixi359 – 3624Combined sources
Helixi366 – 3705Combined sources
Helixi378 – 39417Combined sources
Turni398 – 4014Combined sources
Helixi404 – 4129Combined sources
Beta strandi422 – 4243Combined sources
Helixi426 – 43510Combined sources
Helixi440 – 4423Combined sources
Helixi457 – 4626Combined sources

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
EntryMethodResolution (Å)ChainPositionsPDBsum
4BTFX-ray2.60A1-472[»]
4M68X-ray1.70A182-472[»]
4M69X-ray2.50B182-472[»]
ProteinModelPortaliQ9D2Y4.
SMRiQ9D2Y4. Positions 2-466.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Domaini192 – 456265Protein kinasePROSITE-ProRule annotationAdd
BLAST

Coiled coil

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Coiled coili61 – 8121Sequence analysisAdd
BLAST
Coiled coili138 – 22992Sequence analysisAdd
BLAST

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
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Keywords - Domaini

Coiled coil

Phylogenomic databases

eggNOGiKOG0192. Eukaryota.
COG0515. LUCA.
GeneTreeiENSGT00390000016453.
HOGENOMiHOG000113601.
HOVERGENiHBG056156.
InParanoidiQ9D2Y4.
KOiK08849.
OMAiYKGEYHR.
OrthoDBiEOG091G05XI.
PhylomeDBiQ9D2Y4.
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 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

Alternative sequence

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Alternative sequencei449 – 4568Missing in isoform 2. 2 PublicationsVSP_052132

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

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
EntryMethodResolution (Å)ChainPositionsPDBsum
4BTFX-ray2.60A1-472[»]
4M68X-ray1.70A182-472[»]
4M69X-ray2.50B182-472[»]
ProteinModelPortaliQ9D2Y4.
SMRiQ9D2Y4. Positions 2-466.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

IntActiQ9D2Y4. 2 interactions.
STRINGi10090.ENSMUSP00000113718.

PTM databases

iPTMnetiQ9D2Y4.
PhosphoSiteiQ9D2Y4.

Proteomic databases

MaxQBiQ9D2Y4.
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.
OMAiYKGEYHR.
OrthoDBiEOG091G05XI.
PhylomeDBiQ9D2Y4.
TreeFamiTF328453.

Enzyme and pathway databases

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

Miscellaneous databases

PROiQ9D2Y4.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000012519.
CleanExiMM_MLKL.
ExpressionAtlasiQ9D2Y4. baseline and differential.
GenevisibleiQ9D2Y4. MM.

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_MOUSE
AccessioniPrimary (citable) accession number: Q9D2Y4
Secondary accession number(s): Q8CIJ5
Entry historyi
Integrated into UniProtKB/Swiss-Prot: September 5, 2006
Last sequence update: June 1, 2001
Last modified: September 7, 2016
This is version 122 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

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