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Protein

KH domain-containing, RNA-binding, signal transduction-associated protein 1

Gene

KHDRBS1

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

Functioni

Recruited and tyrosine phosphorylated by several receptor systems, for example the T-cell, leptin and insulin receptors. Once phosphorylated, functions as an adapter protein in signal transduction cascades by binding to SH2 and SH3 domain-containing proteins. Role in G2-M progression in the cell cycle. Represses CBP-dependent transcriptional activation apparently by competing with other nuclear factors for binding to CBP. Also acts as a putative regulator of mRNA stability and/or translation rates and mediates mRNA nuclear export. Positively regulates the association of constitutive transport element (CTE)-containing mRNA with large polyribosomes and translation initiation. According to some authors, is not involved in the nucleocytoplasmic export of unspliced (CTE)-containing RNA species according to (PubMed:22253824). RNA-binding protein that plays a role in the regulation of alternative splicing and influences mRNA splice site selection and exon inclusion. Binds to RNA containing 5'-[AU]UAA-3' as a bipartite motif spaced by more than 15 nucleotides. Binds poly(A). Can regulate CD44 alternative splicing in a Ras pathway-dependent manner (By similarity). In cooperation with HNRNPA1 modulates alternative splicing of BCL2L1 by promoting splicing toward isoform Bcl-X(S), and of SMN1 (PubMed:17371836, PubMed:20186123). Can regulate alternative splicing of NRXN1 and NRXN3 in the laminin G-like domain 6 containing the evolutionary conserved neurexin alternative spliced segment 4 (AS4) involved in neurexin selective targeting to postsynaptic partners. In a neuronal activity-dependent manner cooperates synergistically with KHDRBS2/SLIM-1 in regulation of NRXN1 exon skipping at AS4. The cooperation with KHDRBS2/SLIM-1 is antagonistic for regulation of NXRN3 alternative splicing at AS4 (By similarity).By similarity6 Publications
Isoform 3, which is expressed in growth-arrested cells only, inhibits S phase.1 Publication

GO - Molecular functioni

  • DNA binding Source: ProtInc
  • identical protein binding Source: UniProtKB
  • poly(A) binding Source: MGI
  • poly(U) RNA binding Source: MGI
  • protein-containing complex binding Source: Ensembl
  • protein domain specific binding Source: UniProtKB
  • RNA binding Source: UniProtKB
  • SH3/SH2 adaptor activity Source: UniProtKB
  • SH3 domain binding Source: UniProtKB-KW

GO - Biological processi

  • cell cycle arrest Source: ProtInc
  • cell proliferation Source: ProtInc
  • cell surface receptor signaling pathway Source: UniProtKB
  • G2/M transition of mitotic cell cycle Source: UniProtKB
  • mRNA processing Source: ProtInc
  • negative regulation of transcription, DNA-templated Source: UniProtKB
  • positive regulation of RNA export from nucleus Source: UniProtKB
  • positive regulation of translational initiation Source: UniProtKB
  • protein complex oligomerization Source: UniProtKB
  • regulation of mRNA splicing, via spliceosome Source: Ensembl
  • regulation of RNA export from nucleus Source: UniProtKB
  • signal transduction Source: ProtInc
  • spermatogenesis Source: Ensembl
  • transcription, DNA-templated Source: UniProtKB-KW

Keywordsi

Molecular functionRNA-binding
Biological processCell cycle, mRNA processing, Transcription, Transcription regulation

Enzyme and pathway databases

ReactomeiR-HSA-8849468 PTK6 Regulates Proteins Involved in RNA Processing
SignaLinkiQ07666
SIGNORiQ07666

Names & Taxonomyi

Protein namesi
Recommended name:
KH domain-containing, RNA-binding, signal transduction-associated protein 1
Alternative name(s):
GAP-associated tyrosine phosphoprotein p62
Src-associated in mitosis 68 kDa protein
Short name:
Sam68
p21 Ras GTPase-activating protein-associated p62
p68
Gene namesi
Name:KHDRBS1Imported
Synonyms:SAM681 Publication
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 1

Organism-specific databases

EuPathDBiHostDB:ENSG00000121774.17
HGNCiHGNC:18116 KHDRBS1
MIMi602489 gene
neXtProtiNX_Q07666

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

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi103Y → S: Impairs homodimerization. 1 Publication1
Mutagenesisi110E → A: Impairs homodimerization. 1 Publication1
Mutagenesisi118F → S: Disrupts homodimerization, impairs influence on alternative splicing. 1 Publication1
Mutagenesisi229V → F: Disrupts binding to poly(A), impairs interaction with BCL2L1 modulation of BCL2L1 alternative splicing. 1 Publication1
Mutagenesisi241Y → E: Fails to influence alternative splicing of CD44, NRXN2 and NRXN3. 1 Publication1
Mutagenesisi381E → K: Disrupts interaction with APC. 1 Publication1
Mutagenesisi383Y → K: Impairs interaction with APC. 1 Publication1
Mutagenesisi384E → K: Disrupts interaction with APC. 1 Publication1
Mutagenesisi435Y → F: No effect on the nuclear localization. 1 Publication1
Mutagenesisi440Y → F: Completely blocks nuclear localization. 1 Publication1
Mutagenesisi443Y → F: No effect on the nuclear localization. 1 Publication1

Organism-specific databases

DisGeNETi10657
OpenTargetsiENSG00000121774
PharmGKBiPA30092

Polymorphism and mutation databases

DMDMi62511098

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000501241 – 443KH domain-containing, RNA-binding, signal transduction-associated protein 1Add BLAST443

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei18PhosphoserineCombined sources1
Modified residuei20PhosphoserineCombined sources1
Modified residuei29PhosphoserineCombined sources1
Modified residuei33PhosphothreonineCombined sources1
Modified residuei45Asymmetric dimethylarginine; by PRMT11 Publication1
Modified residuei52Asymmetric dimethylarginine; partial; by PRMT11 Publication1
Modified residuei58PhosphoserineCombined sources1
Modified residuei84Phosphothreonine; by MAPK1By similarity1
Cross-linki96Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Cross-linki102Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei113PhosphoserineBy similarity1
Cross-linki139Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei150PhosphoserineCombined sources1
Modified residuei175N6-acetyllysine; alternateCombined sources1
Cross-linki175Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2); alternateCombined sources
Modified residuei183PhosphothreonineCombined sources1
Modified residuei282Omega-N-methylarginineCombined sources1
Modified residuei284Omega-N-methylarginineCombined sources1
Modified residuei291Omega-N-methylarginineBy similarity1
Modified residuei304Asymmetric dimethylarginine; by PRMT11 Publication1
Modified residuei310Omega-N-methylarginine; by PRMT11 Publication1
Modified residuei315Omega-N-methylarginine; by PRMT11 Publication1
Modified residuei320Dimethylated arginine; in A2780 ovarian carcinoma cell line1 Publication1
Modified residuei320Omega-N-methylarginine; by PRMT11 Publication1
Modified residuei325Omega-N-methylarginine; by PRMT11 Publication1
Modified residuei331Asymmetric dimethylarginine; alternateBy similarity1
Modified residuei331Dimethylated arginine; in A2780 ovarian carcinoma cell line1 Publication1
Modified residuei331Omega-N-methylarginine; alternateCombined sources1
Modified residuei331Omega-N-methylated arginine; by PRMT1; alternate1 Publication1
Modified residuei340Dimethylated arginine; in A2780 ovarian carcinoma cell line1 Publication1
Modified residuei340Omega-N-methylarginine; by PRMT1Combined sources1
Modified residuei387Phosphotyrosine1 Publication1
Modified residuei390PhosphoserineCombined sources1
Cross-linki432Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in SUMO2)Combined sources
Modified residuei435Phosphotyrosine; by PTK61 Publication1
Modified residuei440Phosphotyrosine; by PTK61 Publication1
Modified residuei443Phosphotyrosine; by PTK61 Publication1

Post-translational modificationi

Tyrosine phosphorylated by several non-receptor tyrosine kinases including LCK, FYN and JAK3. Also tyrosine phosphorylated by the non-receptor tyrosine kinase SRMS in an EGF-dependent manner (PubMed:29496907). Negatively correlates with ability to bind RNA but required for many interactions with proteins. Phosphorylation by PTK6 negatively regulates its RNA binding ability. Phosphorylation by PTK6 at Tyr-440 dictates the nuclear localization of KHDRBS1. Phosphorylation at Tyr-387 disrupts interaction with APC. Phosphorylation at tyrosine residues by FYN inverts activity on modulation of BCL2L1 alternative splicing.6 Publications
Acetylated. Positively correlates with ability to bind RNA.1 Publication
Arginine methylation is required for nuclear localization. Also can affect interaction with other proteins. Inhibits interaction with Src-like SH3 domains, but not interaction with WW domains of WBP4/FBP21 AND FNBP4/FBP30.3 Publications

Keywords - PTMi

Acetylation, Isopeptide bond, Methylation, Phosphoprotein, Ubl conjugation

Proteomic databases

EPDiQ07666
MaxQBiQ07666
PaxDbiQ07666
PeptideAtlasiQ07666
PRIDEiQ07666
ProteomicsDBi58523
58524 [Q07666-2]
58525 [Q07666-3]
TopDownProteomicsiQ07666-1 [Q07666-1]
Q07666-3 [Q07666-3]

PTM databases

iPTMnetiQ07666
PhosphoSitePlusiQ07666
SwissPalmiQ07666

Miscellaneous databases

PMAP-CutDBiQ07666

Expressioni

Tissue specificityi

Ubiquitously expressed in all tissue examined. Isoform 1 is expressed at lower levels in brain, skeletal muscle, and liver whereas isoform 3 is intensified in skeletal muscle and in liver.1 Publication

Developmental stagei

Isoform 3 is only expressed in growth-arrested cells.1 Publication

Gene expression databases

BgeeiENSG00000121774
CleanExiHS_KHDRBS1
GenevisibleiQ07666 HS

Organism-specific databases

HPAiCAB005355
HPA051280
HPA056813

Interactioni

Subunit structurei

Self-associates to form homooligomers when bound to RNA, oligomerization appears to be limited when binding to proteins; dimerization increases RNA affinity (PubMed:26758068, PubMed:20610388). Interacts with KHDRBS3/SLIM-2 (PubMed:10332027). Interacts with KHDRBS2/SLIM-1; heterooligomer formation of KHDRBS family proteins may modulate RNA substrate specificity (By similarity). Interacts with RASA1, LCK, FYN, PTPN6, PLCG1, GRB2, CBL, JAK3, PIK3R, STAT3, APC, HNRNPA1 (PubMed:1374686, PubMed:9045636, PubMed:10332027, PubMed:11585385, PubMed:17371836, PubMed:22000517). Interacts with PTK6 (via SH3 and SH2 domains) (PubMed:10913193). Forms a complex with ILF2, ILF3, YLPM1, RBMX, NCOA5 and PPP1CA (PubMed:17890166). Does not interact with TPR (PubMed:22253824). Interacts with RBMY1A1, PRMT1 (By similarity). Binds WBP4/FBP21 (via WW domains), FNBP4/FBP30 (via WW domains). Interacts (via Arg/Gly-rich-flanked Pro-rich regions) with FYN (via the SH3 domain) (By similarity). Interacts with the non-receptor tyrosine kinase SRMS; the interaction leads to phosphorylation of KHDRBS1 (PubMed:29496907).By similarity9 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • identical protein binding Source: UniProtKB
  • protein domain specific binding Source: UniProtKB
  • SH3/SH2 adaptor activity Source: UniProtKB
  • SH3 domain binding Source: UniProtKB-KW

Protein-protein interaction databases

BioGridi115900, 174 interactors
CORUMiQ07666
DIPiDIP-29007N
IntActiQ07666, 81 interactors
MINTiQ07666
STRINGi9606.ENSP00000313829

Structurei

Secondary structure

1443
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi100 – 113Combined sources14
Helixi119 – 134Combined sources16

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2XA6NMR-A/B97-135[»]
3QHEX-ray2.40B/D365-419[»]
ProteinModelPortaliQ07666
SMRiQ07666
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiQ07666

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini171 – 197KHPROSITE-ProRule annotationAdd BLAST27

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni100 – 260Involved in homodimerization1 PublicationAdd BLAST161
Regioni351 – 443Interaction with HNRNPA11 PublicationAdd BLAST93

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi34 – 41Pro-richSequence analysis8
Compositional biasi44 – 55DMA/Gly-richSequence analysisAdd BLAST12
Compositional biasi59 – 89Pro-richSequence analysisAdd BLAST31
Compositional biasi282 – 292DMA/Gly-richSequence analysisAdd BLAST11
Compositional biasi295 – 301Pro-richSequence analysis7
Compositional biasi302 – 332Arg/Gly-richSequence analysisAdd BLAST31
Compositional biasi334 – 363Pro-richSequence analysisAdd BLAST30

Domaini

The KH domain is required for binding to RNA.By similarity
The Pro-rich domains are flanked by Arg/Gly-rich motifs which can be asymmetric dimethylated on arginine residues to give the DMA/Gly-rich regions. Selective methylation on these motifs can modulate protein-protein interactions (By similarity).By similarity

Sequence similaritiesi

Belongs to the KHDRBS family.Sequence analysis

Keywords - Domaini

SH3-binding

Phylogenomic databases

eggNOGiKOG1588 Eukaryota
COG5176 LUCA
GeneTreeiENSGT00550000074434
HOGENOMiHOG000230771
HOVERGENiHBG079164
InParanoidiQ07666
KOiK13198
OMAiFLFPDMM
OrthoDBiEOG091G0EED
PhylomeDBiQ07666
TreeFamiTF314878

Family and domain databases

Gene3Di3.30.1370.10, 1 hit
InterProiView protein in InterPro
IPR004087 KH_dom
IPR004088 KH_dom_type_1
IPR036612 KH_dom_type_1_sf
IPR032571 Qua1_dom
IPR032335 Sam68-YY
PfamiView protein in Pfam
PF00013 KH_1, 1 hit
PF16274 Qua1, 1 hit
PF16568 Sam68-YY, 1 hit
SMARTiView protein in SMART
SM00322 KH, 1 hit
SUPFAMiSSF54791 SSF54791, 1 hit
PROSITEiView protein in PROSITE
PS50084 KH_TYPE_1, 1 hit

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 11 Publication (identifier: Q07666-1) [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
MQRRDDPAAR MSRSSGRSGS MDPSGAHPSV RQTPSRQPPL PHRSRGGGGG
60 70 80 90 100
SRGGARASPA TQPPPLLPPS ATGPDATVGG PAPTPLLPPS ATASVKMEPE
110 120 130 140 150
NKYLPELMAE KDSLDPSFTH AMQLLTAEIE KIQKGDSKKD DEENYLDLFS
160 170 180 190 200
HKNMKLKERV LIPVKQYPKF NFVGKILGPQ GNTIKRLQEE TGAKISVLGK
210 220 230 240 250
GSMRDKAKEE ELRKGGDPKY AHLNMDLHVF IEVFGPPCEA YALMAHAMEE
260 270 280 290 300
VKKFLVPDMM DDICQEQFLE LSYLNGVPEP SRGRGVPVRG RGAAPPPPPV
310 320 330 340 350
PRGRGVGPPR GALVRGTPVR GAITRGATVT RGVPPPPTVR GAPAPRARTA
360 370 380 390 400
GIQRIPLPPP PAPETYEEYG YDDTYAEQSY EGYEGYYSQS QGDSEYYDYG
410 420 430 440
HGEVQDSYEA YGQDDWNGTR PSLKAPPARP VKGAYREHPY GRY
Length:443
Mass (Da):48,227
Last modified:November 1, 1996 - v1
Checksum:i59FB4DB6FB4DBE98
GO
Isoform 2Curated (identifier: Q07666-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     37-61: Missing.

Note: No experimental confirmation available.Curated
Show »
Length:418
Mass (Da):45,861
Checksum:i36B5B877E35D9A2C
GO
Isoform 31 Publication (identifier: Q07666-3) [UniParc]FASTAAdd to basket
Also known as: DeltaKH1 Publication

The sequence of this isoform differs from the canonical sequence as follows:
     169-207: Missing.

Show »
Length:404
Mass (Da):44,027
Checksum:i0E6334E3447CCA5F
GO

Sequence cautioni

The sequence AAH10132 differs from that shown. Intron retention.Curated

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_05171937 – 61Missing in isoform 2. 1 PublicationAdd BLAST25
Alternative sequenceiVSP_051720169 – 207Missing in isoform 3. 1 PublicationAdd BLAST39

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
M88108 mRNA Translation: AAA59990.1
U78971 mRNA Translation: AAB47504.1
AK091346 mRNA Translation: BAC03643.1
AL139249, AL445248 Genomic DNA Translation: CAI21971.1
AL139249, AL445248 Genomic DNA Translation: CAI21972.1
AL445248, AL139249 Genomic DNA Translation: CAH71944.1
AL445248, AL139249 Genomic DNA Translation: CAH71945.1
CH471059 Genomic DNA Translation: EAX07576.1
CH471059 Genomic DNA Translation: EAX07577.1
BC000717 mRNA Translation: AAH00717.1
BC010132 mRNA Translation: AAH10132.1 Sequence problems.
BC019109 mRNA Translation: AAH19109.1
CCDSiCCDS350.1 [Q07666-1]
CCDS60067.1 [Q07666-3]
PIRiA38219
RefSeqiNP_001258807.1, NM_001271878.1 [Q07666-3]
NP_006550.1, NM_006559.2 [Q07666-1]
UniGeneiHs.445893

Genome annotation databases

EnsembliENST00000327300; ENSP00000313829; ENSG00000121774 [Q07666-1]
ENST00000492989; ENSP00000417731; ENSG00000121774 [Q07666-3]
GeneIDi10657
KEGGihsa:10657
UCSCiuc001bua.3 human [Q07666-1]

Keywords - Coding sequence diversityi

Alternative splicing

Similar proteinsi

Entry informationi

Entry nameiKHDR1_HUMAN
AccessioniPrimary (citable) accession number: Q07666
Secondary accession number(s): D3DPP3
, Q6PJX7, Q8NB97, Q99760
Entry historyiIntegrated into UniProtKB/Swiss-Prot: April 12, 2005
Last sequence update: November 1, 1996
Last modified: June 20, 2018
This is version 185 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, Direct protein sequencing, Reference proteome

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