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Protein

Kinase suppressor of Ras 2

Gene

KSR2

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

Functioni

Location-regulated scaffold connecting MEK to RAF. Has very low protein kinase activity and can phosphorylate MAP2K1 at several Ser and Thr residues with very low efficiency (in vitro). Interaction with BRAF enhances KSR2-mediated phosphorylation of MAP2K1 (in vitro). Blocks MAP3K8 kinase activity and MAP3K8-mediated signaling. Acts as a negative regulator of MAP3K3-mediated activation of ERK, JNK and NF-kappa-B pathways, inhibiting MAP3K3-mediated interleukin-8 production.3 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.1 Publication

Enzyme regulationi

Kinase activity is inhibited by ASC24.1 Publication

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi413Zinc 1By similarity1
Metal bindingi425Zinc 2By similarity1
Metal bindingi428Zinc 2By similarity1
Metal bindingi438Zinc 1By similarity1
Metal bindingi441Zinc 1By similarity1
Metal bindingi446Zinc 2By similarity1
Metal bindingi449Zinc 2By similarity1
Metal bindingi456Zinc 1By similarity1
Active sitei786Proton donor/acceptor1 Publication1
Binding sitei788ATP1 Publication1
Binding sitei803ATP1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri412 – 456Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST45
Nucleotide bindingi672 – 680ATPPROSITE-ProRule annotation1 Publication9

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Kinase, Serine/threonine-protein kinase, Transferase

Keywords - Ligandi

ATP-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDAi2.7.11.25. 2681.
ReactomeiR-HSA-5674135. MAP2K and MAPK activation.
R-HSA-6802946. Signaling by moderate kinase activity BRAF mutants.
R-HSA-6802948. Signaling by high-kinase activity BRAF mutants.
R-HSA-6802949. Signaling by RAS mutants.
R-HSA-6802952. Signaling by BRAF and RAF fusions.
R-HSA-6802955. Paradoxical activation of RAF signaling by kinase inactive BRAF.
SignaLinkiQ6VAB6.
SIGNORiQ6VAB6.

Names & Taxonomyi

Protein namesi
Recommended name:
Kinase suppressor of Ras 2 (EC:2.7.11.1)
Short name:
hKSR2
Gene namesi
Name:KSR2
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 12

Organism-specific databases

HGNCiHGNC:18610. KSR2.

Subcellular locationi

GO - Cellular componenti

Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi718R → H: Impairs formation of heterotetramers with MAP2K1, but not the formation of heterodimers. 1 Publication1
Mutagenesisi786D → A: Loss of kinase activity. 1 Publication1
Mutagenesisi879A → L: Impairs MAP2K1 binding. 1 Publication1

Organism-specific databases

DisGeNETi283455.
OpenTargetsiENSG00000171435.
PharmGKBiPA134914125.

Chemistry databases

ChEMBLiCHEMBL3627583.

Polymorphism and mutation databases

BioMutaiKSR2.
DMDMi148886599.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000862311 – 950Kinase suppressor of Ras 2Add BLAST950

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei272PhosphothreonineBy similarity1
Modified residuei276PhosphothreonineBy similarity1
Modified residuei474Phosphoserine; by MARK3By similarity1
Modified residuei497PhosphothreonineBy similarity1

Post-translational modificationi

Phosphorylated on Ser-474 by MARK3.By similarity

Keywords - PTMi

Phosphoprotein

Proteomic databases

PaxDbiQ6VAB6.
PeptideAtlasiQ6VAB6.
PRIDEiQ6VAB6.

PTM databases

iPTMnetiQ6VAB6.
PhosphoSitePlusiQ6VAB6.

Expressioni

Tissue specificityi

Mainly expressed in brain and kidney.1 Publication

Gene expression databases

BgeeiENSG00000171435.
CleanExiHS_KSR2.
ExpressionAtlasiQ6VAB6. baseline and differential.
GenevisibleiQ6VAB6. HS.

Organism-specific databases

HPAiHPA035536.

Interactioni

Subunit structurei

Interacts with MAP2K1, forming a heterodimer that can dimerize to form a heterotetramer. Interacts with MAP3K8, MAPK, RAS and RAF. Interacts with BRAF; this increases the low intrinsic protein kinase activity of KSR2.2 Publications

Protein-protein interaction databases

BioGridi129567. 4 interactors.
DIPiDIP-59195N.
IntActiQ6VAB6. 11 interactors.
MINTiMINT-8397064.
STRINGi9606.ENSP00000339952.

Structurei

Secondary structure

1950
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi656 – 658Combined sources3
Beta strandi659 – 661Combined sources3
Beta strandi675 – 693Combined sources19
Turni704 – 710Combined sources7
Helixi711 – 714Combined sources4
Beta strandi727 – 730Combined sources4
Beta strandi735 – 738Combined sources4
Beta strandi744 – 746Combined sources3
Helixi747 – 750Combined sources4
Helixi761 – 779Combined sources19
Beta strandi792 – 794Combined sources3
Helixi827 – 830Combined sources4
Helixi834 – 837Combined sources4
Helixi853 – 869Combined sources17
Beta strandi873 – 876Combined sources4
Helixi879 – 887Combined sources9
Helixi903 – 911Combined sources9
Turni915 – 917Combined sources3
Helixi921 – 928Combined sources8

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y4IX-ray3.46B634-950[»]
5KKRX-ray3.51B634-950[»]
ProteinModelPortaliQ6VAB6.
SMRiQ6VAB6.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini666 – 931Protein kinasePROSITE-ProRule annotationAdd BLAST266

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi181 – 293Pro-richAdd BLAST113
Compositional biasi510 – 550Pro-richAdd BLAST41

Domaini

The protein kinase domain is predicted to be catalytically inactive and seems to have very low intrinsic kinase activity. This low kinase activity can be increased by interaction with BRAF.

Sequence similaritiesi

Contains 1 phorbol-ester/DAG-type zinc finger.PROSITE-ProRule annotation
Contains 1 protein kinase domain.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri412 – 456Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST45

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG0193. Eukaryota.
ENOG410Y4UP. LUCA.
GeneTreeiENSGT00760000118807.
HOGENOMiHOG000113263.
HOVERGENiHBG052293.
InParanoidiQ6VAB6.
KOiK18529.
OMAiKCIQHYC.
OrthoDBiEOG091G02ZN.
PhylomeDBiQ6VAB6.
TreeFamiTF317006.

Family and domain databases

CDDicd00029. C1. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR025561. KSR_SAM-like_dom.
IPR002219. PE/DAG-bd.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF13543. KSR1-SAM. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SMARTiSM00109. C1. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS00479. ZF_DAG_PE_1. 1 hit.
PS50081. ZF_DAG_PE_2. 1 hit.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

Isoform 1 (identifier: Q6VAB6-1) [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
MDEENMTKSE EQQPLSLQKA LQQCELVQNM IDLSISNLEG LRTKCATSND
60 70 80 90 100
LTQKEIRTLE SKLVKYFSRQ LSCKKKVALQ ERNAELDGFP QLRHWFRIVD
110 120 130 140 150
VRKEVLEEIS PGQLSLEDLL EMTDEQVCET VEKYGANREE CARLNASLSC
160 170 180 190 200
LRNVHMSGGN LSKQDWTIQW PTTETGKENN PVCPPEPTPW IRTHLSQSPR
210 220 230 240 250
VPSKCVQHYC HTSPTPGAPV YTHVDRLTVD AYPGLCPPPP LESGHRSLPP
260 270 280 290 300
SPRQRHAVRT PPRTPNIVTT VTPPGTPPMR KKNKLKPPGT PPPSSRKLIH
310 320 330 340 350
LIPGFTALHR SKSHEFQLGH RVDEAHTPKA KKKSKPLNLK IHSSVGSCEN
360 370 380 390 400
IPSQQRSPLL SERSLRSFFV GHAPFLPSTP PVHTEANFSA NTLSVPRWSP
410 420 430 440 450
QIPRRDLGNS IKHRFSTKYW MSQTCTVCGK GMLFGLKCKN CKLKCHNKCT
460 470 480 490 500
KEAPPCHLLI IHRGDPARLV RTESVPCDIN NPLRKPPRYS DLHISQTLPK
510 520 530 540 550
TNKINKDHIP VPYQPDSSSN PSSTTSSTPS SPAPPLPPSA TPPSPLHPSP
560 570 580 590 600
QCTRQQKNFN LPASHYYKYK QQFIFPDVVP VPETPTRAPQ VILHPVTSNP
610 620 630 640 650
ILEGNPLLQI EVEPTSENEE VHDEAEESED DFEEMNLSLL SARSFPRKAS
660 670 680 690 700
QTSIFLQEWD IPFEQLEIGE LIGKGRFGQV YHGRWHGEVA IRLIDIERDN
710 720 730 740 750
EDQLKAFKRE VMAYRQTRHE NVVLFMGACM SPPHLAIITS LCKGRTLYSV
760 770 780 790 800
VRDAKIVLDV NKTRQIAQEI VKGMGYLHAK GILHKDLKSK NVFYDNGKVV
810 820 830 840 850
ITDFGLFSIS GVLQAGRRED KLRIQNGWLC HLAPEIIRQL SPDTEEDKLP
860 870 880 890 900
FSKHSDVFAL GTIWYELHAR EWPFKTQPAE AIIWQMGTGM KPNLSQIGMG
910 920 930 940 950
KEISDILLFC WAFEQEERPT FTKLMDMLEK LPKRNRRLSH PGHFWKSAEL
Length:950
Mass (Da):107,632
Last modified:May 29, 2007 - v2
Checksum:iDFBC20F4E71077AD
GO
Isoform 2 (identifier: Q6VAB6-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-303: Missing.
     304-329: GFTALHRSKSHEFQLGHRVDEAHTPK → MYNKKAKMEPNASESAIPARRQRQPR
     740-742: SLC → RPV
     743-950: Missing.

Show »
Length:439
Mass (Da):49,607
Checksum:iA5D6F1DEAFDA51FC
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_040659676R → S in a lung adenocarcinoma sample; somatic mutation. 1 Publication1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0122341 – 303Missing in isoform 2. 1 PublicationAdd BLAST303
Alternative sequenceiVSP_012235304 – 329GFTAL…AHTPK → MYNKKAKMEPNASESAIPAR RQRQPR in isoform 2. 1 PublicationAdd BLAST26
Alternative sequenceiVSP_012236740 – 742SLC → RPV in isoform 2. 1 Publication3
Alternative sequenceiVSP_012237743 – 950Missing in isoform 2. 1 PublicationAdd BLAST208

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK098831 mRNA. Translation: BAC05426.1.
AC073864 Genomic DNA. No translation available.
AC079127 Genomic DNA. No translation available.
AC084291 Genomic DNA. No translation available.
AC092936 Genomic DNA. No translation available.
AY345972 mRNA. Translation: AAQ24226.1.
BC107106 mRNA. Translation: AAI07107.1.
BC107107 mRNA. Translation: AAI07108.1.
BC127603 mRNA. Translation: AAI27604.1.
RefSeqiNP_775869.3. NM_173598.4.
XP_011536527.1. XM_011538225.2.
UniGeneiHs.375836.

Genome annotation databases

EnsembliENST00000339824; ENSP00000339952; ENSG00000171435. [Q6VAB6-1]
GeneIDi283455.
KEGGihsa:283455.
UCSCiuc058tua.1. human. [Q6VAB6-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK098831 mRNA. Translation: BAC05426.1.
AC073864 Genomic DNA. No translation available.
AC079127 Genomic DNA. No translation available.
AC084291 Genomic DNA. No translation available.
AC092936 Genomic DNA. No translation available.
AY345972 mRNA. Translation: AAQ24226.1.
BC107106 mRNA. Translation: AAI07107.1.
BC107107 mRNA. Translation: AAI07108.1.
BC127603 mRNA. Translation: AAI27604.1.
RefSeqiNP_775869.3. NM_173598.4.
XP_011536527.1. XM_011538225.2.
UniGeneiHs.375836.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2Y4IX-ray3.46B634-950[»]
5KKRX-ray3.51B634-950[»]
ProteinModelPortaliQ6VAB6.
SMRiQ6VAB6.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi129567. 4 interactors.
DIPiDIP-59195N.
IntActiQ6VAB6. 11 interactors.
MINTiMINT-8397064.
STRINGi9606.ENSP00000339952.

Chemistry databases

ChEMBLiCHEMBL3627583.

PTM databases

iPTMnetiQ6VAB6.
PhosphoSitePlusiQ6VAB6.

Polymorphism and mutation databases

BioMutaiKSR2.
DMDMi148886599.

Proteomic databases

PaxDbiQ6VAB6.
PeptideAtlasiQ6VAB6.
PRIDEiQ6VAB6.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000339824; ENSP00000339952; ENSG00000171435. [Q6VAB6-1]
GeneIDi283455.
KEGGihsa:283455.
UCSCiuc058tua.1. human. [Q6VAB6-1]

Organism-specific databases

CTDi283455.
DisGeNETi283455.
GeneCardsiKSR2.
H-InvDBHIX0018992.
HGNCiHGNC:18610. KSR2.
HPAiHPA035536.
MIMi610737. gene.
neXtProtiNX_Q6VAB6.
OpenTargetsiENSG00000171435.
PharmGKBiPA134914125.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0193. Eukaryota.
ENOG410Y4UP. LUCA.
GeneTreeiENSGT00760000118807.
HOGENOMiHOG000113263.
HOVERGENiHBG052293.
InParanoidiQ6VAB6.
KOiK18529.
OMAiKCIQHYC.
OrthoDBiEOG091G02ZN.
PhylomeDBiQ6VAB6.
TreeFamiTF317006.

Enzyme and pathway databases

BRENDAi2.7.11.25. 2681.
ReactomeiR-HSA-5674135. MAP2K and MAPK activation.
R-HSA-6802946. Signaling by moderate kinase activity BRAF mutants.
R-HSA-6802948. Signaling by high-kinase activity BRAF mutants.
R-HSA-6802949. Signaling by RAS mutants.
R-HSA-6802952. Signaling by BRAF and RAF fusions.
R-HSA-6802955. Paradoxical activation of RAF signaling by kinase inactive BRAF.
SignaLinkiQ6VAB6.
SIGNORiQ6VAB6.

Miscellaneous databases

ChiTaRSiKSR2. human.
GenomeRNAii283455.
PROiQ6VAB6.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000171435.
CleanExiHS_KSR2.
ExpressionAtlasiQ6VAB6. baseline and differential.
GenevisibleiQ6VAB6. HS.

Family and domain databases

CDDicd00029. C1. 1 hit.
InterProiIPR011009. Kinase-like_dom.
IPR025561. KSR_SAM-like_dom.
IPR002219. PE/DAG-bd.
IPR000719. Prot_kinase_dom.
IPR001245. Ser-Thr/Tyr_kinase_cat_dom.
IPR008271. Ser/Thr_kinase_AS.
[Graphical view]
PfamiPF13543. KSR1-SAM. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]
SMARTiSM00109. C1. 1 hit.
SM00220. S_TKc. 1 hit.
[Graphical view]
SUPFAMiSSF56112. SSF56112. 1 hit.
PROSITEiPS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS00479. ZF_DAG_PE_1. 1 hit.
PS50081. ZF_DAG_PE_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiKSR2_HUMAN
AccessioniPrimary (citable) accession number: Q6VAB6
Secondary accession number(s): A0PJT2, Q3B828, Q8N775
Entry historyi
Integrated into UniProtKB/Swiss-Prot: December 21, 2004
Last sequence update: May 29, 2007
Last modified: November 30, 2016
This is version 115 of the entry and version 2 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

Caution

KSR2 binds ATP and has very low in vitro protein kinase activity; the physiological relevance of this activity is unknown. KSR2 is proposed to be in an inactive conformation by itself or in complex with MAP2K1. Interaction with BRAF is proposed to induce a conformation change that increases the low intrinsic kinase activity (PubMed:21441910).1 Publication

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: 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.