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Protein

Cysteine and glycine-rich protein 3

Gene

CSRP3

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

Functioni

Positive regulator of myogenesis. Acts as cofactor for myogenic bHLH transcription factors such as MYOD1, and probably MYOG and MYF6. Enhances the DNA-binding activity of the MYOD1:TCF3 isoform E47 complex and may promote formation of a functional MYOD1:TCF3 isoform E47:MEF2A complex involved in myogenesis (By similarity). Plays a crucial and specific role in the organization of cytosolic structures in cardiomyocytes. Could play a role in mechanical stretch sensing. May be a scaffold protein that promotes the assembly of interacting proteins at Z-line structures. It is essential for calcineurin anchorage to the Z line. Required for stress-induced calcineurin-NFAT activation (By similarity). The role in regulation of cytoskeleton dynamics by association with CFL2 is reported conflictingly: Shown to enhance CFL2-mediated F-actin depolymerization dependent on the CSRP3:CFL2 molecular ratio, and also shown to reduce the ability of CLF1 and CFL2 to enhance actin depolymerization (PubMed:19752190, PubMed:24934443). Proposed to contribute to the maintenance of muscle cell integerity through an actin-based mechanism. Can directly bind to actin filaments, cross-link actin filaments into bundles without polarity selectivity and protect them from dilution- and cofilin-mediated depolymerization; the function seems to involve its self-association (PubMed:24934443). In vitro can inhibit PKC/PRKCA activity (PubMed:27353086). Proposed to be involved in cardiac stress signaling by down-regulating excessive PKC/PRKCA signaling (By similarity).By similarity3 Publications
Isoform 2: May play a role in early sarcomere organization. Overexpression in myotubes negatively regulates myotube differentiation. By association with isoform 1 and thus changing the CSRP3 isoform 1:CFL2 stoichiometry is proposed to down-regulate CFL2-mediated F-actin depolymerization.1 Publication

GO - Molecular functioni

  • actinin binding Source: BHF-UCL
  • structural constituent of muscle Source: BHF-UCL
  • telethonin binding Source: BHF-UCL
  • zinc ion binding Source: InterPro

GO - Biological processi

  • cardiac muscle contraction Source: BHF-UCL
  • cardiac muscle hypertrophy Source: BHF-UCL
  • cardiac muscle tissue development Source: BHF-UCL
  • cardiac myofibril assembly Source: BHF-UCL
  • cellular calcium ion homeostasis Source: BHF-UCL
  • detection of muscle stretch Source: BHF-UCL
  • negative regulation of actin filament severing Source: MGI
  • negative regulation of myoblast differentiation Source: MGI
  • positive regulation of actin filament severing Source: MGI
  • positive regulation of myoblast differentiation Source: MGI
  • positive regulation of transcription from RNA polymerase II promoter Source: MGI
  • protein localization to organelle Source: BHF-UCL
  • regulation of the force of heart contraction Source: BHF-UCL
  • skeletal muscle tissue development Source: ProtInc
  • transcription, DNA-templated Source: UniProtKB-KW
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Keywords - Biological processi

Differentiation, Myogenesis, Transcription, Transcription regulation

Keywords - Ligandi

Actin-binding, Metal-binding, Zinc

Enzyme and pathway databases

BioCyciZFISH:ENSG00000129170-MONOMER.
SIGNORiP50461.

Names & Taxonomyi

Protein namesi
Recommended name:
Cysteine and glycine-rich protein 3
Alternative name(s):
Cardiac LIM protein
Cysteine-rich protein 3
Short name:
CRP3
LIM domain protein, cardiac
Muscle LIM protein
Gene namesi
Name:CSRP3
Synonyms:CLP, MLP
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 11

Organism-specific databases

HGNCiHGNC:2472. CSRP3.

Subcellular locationi

Isoform 2 :

GO - Cellular componenti

  • cytoskeleton Source: UniProtKB-SubCell
  • nucleus Source: UniProtKB-SubCell
  • Z disc Source: BHF-UCL
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Cytoskeleton, Nucleus

Pathology & Biotechi

Involvement in diseasei

Cardiomyopathy, dilated 1M (CMD1M)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
See also OMIM:607482
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0154014W → R in CMD1M; unknown pathological significance; decreases interaction with TCAP. 2 PublicationsCorresponds to variant rs45550635dbSNPEnsembl.1
Natural variantiVAR_07680572G → R in CMD1M; unknown pathological significance; increases PKC/PRKCA activity. 2 Publications1
Cardiomyopathy, familial hypertrophic 12 (CMH12)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.
See also OMIM:612124
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04593244L → P in CMH12; decreases PKC/PRKCA activity. 2 PublicationsCorresponds to variant rs104894205dbSNPEnsembl.1
Natural variantiVAR_04593354 – 55SE → RG in CMH12; decreases PKC/PRKCA activity. 1 PublicationCorresponds to variant rs281865416dbSNPEnsembl.2
Natural variantiVAR_04593458C → G in CMH12; decreases interaction with NRAP and ACTN2, decreases zinc-binding and impairs protein stability, decreases PKC/PRKCA activity. 3 PublicationsCorresponds to variant rs104894204dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi69K → R: Increases PKC/PRKCA activity. 1 Publication1

Keywords - Diseasei

Cardiomyopathy, Disease mutation

Organism-specific databases

DisGeNETi8048.
MalaCardsiCSRP3.
MIMi607482. phenotype.
612124. phenotype.
OpenTargetsiENSG00000129170.
Orphaneti154. Familial isolated dilated cardiomyopathy.
155. Familial isolated hypertrophic cardiomyopathy.
PharmGKBiPA26971.

Polymorphism and mutation databases

BioMutaiCSRP3.
DMDMi1705933.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000757271 – 194Cysteine and glycine-rich protein 3Add BLAST194

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei95PhosphoserineBy similarity1
Modified residuei153PhosphoserineBy similarity1

Post-translational modificationi

Phosphorylated by PKC/PRKCA.1 Publication

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiP50461.
MaxQBiP50461.
PaxDbiP50461.
PeptideAtlasiP50461.
PRIDEiP50461.

PTM databases

iPTMnetiP50461.
PhosphoSitePlusiP50461.

Expressioni

Tissue specificityi

Cardiac and slow-twitch skeletal muscles. Isoform 2 is expressed in striated muscle. Isoform 2 is specifically expressed at higher levels in patients with neuromuscular diseases, such as limb-girdle muscular dystrophy 2A (LGMD2A), Duchenne muscular dystrophy (DMD) and dermatomyositis (PubMed:24860983).1 Publication

Gene expression databases

BgeeiENSG00000129170.
CleanExiHS_CSRP3.
ExpressionAtlasiP50461. baseline and differential.
GenevisibleiP50461. HS.

Organism-specific databases

HPAiHPA042581.

Interactioni

Subunit structurei

Self-associates. Oligomeric in the cytoplasm and monomeric in the nucleus (By similarity). Homooligomers preferentially form along the actin cytoskeleton. Isoform 2 interacts with isoform 1 (PubMed:24934443, PubMed:24860983). Isoform 1 but not isoform 2 interacts with MYOD1 and MYOG. Isoform 1 interacts with TCAP, ACTN2 and NRAP. Isoform 2 interacts with TCAP and alpha-actinin (PubMed:24860983, PubMed:15582318, PubMed:15205937, PubMed:12507422). Interacts with LDHD. Interacts (via N-terminus)with GLRX3 (via C-terminus) and PPP3CA; GLRX3 and calcineurin compete for interaction with CSRP3. Interacts with MYF6 (By similarity). Interacts with CFL2; the stoichiometry influences F-actin depolymerization and possibly two molecules of CFL2 can interact with one molecule of CSRP3 resulting in the highest functional impact; the interaction is stronger with phosphorylated CFL2 (PubMed:19752190).By similarity6 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
S4S7M72EBI-5658719,EBI-9540516
ACTN2P356094EBI-5658719,EBI-77797
CFL2Q9Y2812EBI-5658719,EBI-351218
NRAPQ86VF72EBI-5658719,EBI-5660292
TCAPO152733EBI-5658719,EBI-954089

GO - Molecular functioni

  • actinin binding Source: BHF-UCL
  • telethonin binding Source: BHF-UCL

Protein-protein interaction databases

BioGridi113736. 7 interactors.
IntActiP50461. 10 interactors.
STRINGi9606.ENSP00000265968.

Structurei

Secondary structure

1194
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi14 – 17Combined sources4
Helixi19 – 21Combined sources3
Beta strandi22 – 25Combined sources4
Beta strandi28 – 31Combined sources4
Turni32 – 34Combined sources3
Beta strandi38 – 40Combined sources3
Turni46 – 48Combined sources3
Beta strandi50 – 52Combined sources3
Beta strandi55 – 57Combined sources3
Helixi59 – 65Combined sources7
Turni121 – 124Combined sources4
Turni129 – 131Combined sources3
Beta strandi133 – 135Combined sources3
Beta strandi138 – 140Combined sources3
Turni142 – 144Combined sources3
Beta strandi145 – 147Combined sources3
Turni148 – 151Combined sources4
Beta strandi159 – 162Combined sources4
Beta strandi165 – 168Combined sources4
Helixi169 – 175Combined sources7

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2O10NMR-A7-66[»]
2O13NMR-A119-176[»]
ProteinModelPortaliP50461.
SMRiP50461.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP50461.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini10 – 61LIM zinc-binding 1PROSITE-ProRule annotationAdd BLAST52
Domaini120 – 171LIM zinc-binding 2PROSITE-ProRule annotationAdd BLAST52

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni1 – 5Interaction with TCAP1 Publication5
Regioni94 – 105Interaction with CLF2 and isoform 22 PublicationsAdd BLAST12

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi64 – 69Nuclear localization signalSequence analysisBy similarity6

Compositional bias

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Compositional biasi63 – 78Gly-richAdd BLAST16
Compositional biasi177 – 185Gly-rich9

Domaini

LIM zinc-binding domain 1 is required for self-association. LIM zinc-binding domain 1 and LIM zinc-binding domain 2 both are required for optimal actin-bundling activity (PubMed:24934443). LIM zinc-binding domain 1 mediates binding to MYOD1. LIM zinc-binding domain 2 mediates binding to SPTB (By similarity).By similarity1 Publication

Sequence similaritiesi

Contains 2 LIM zinc-binding domains.PROSITE-ProRule annotation

Keywords - Domaini

LIM domain, Repeat

Phylogenomic databases

eggNOGiENOG410ITI8. Eukaryota.
ENOG410Z840. LUCA.
GeneTreeiENSGT00550000074548.
HOGENOMiHOG000111233.
HOVERGENiHBG051143.
InParanoidiP50461.
KOiK09377.
OMAiQSPKQAR.
OrthoDBiEOG091G11RX.
PhylomeDBiP50461.
TreeFamiTF313758.

Family and domain databases

Gene3Di2.10.110.10. 2 hits.
InterProiIPR001781. Znf_LIM.
[Graphical view]
PfamiPF00412. LIM. 2 hits.
[Graphical view]
SMARTiSM00132. LIM. 2 hits.
[Graphical view]
PROSITEiPS00478. LIM_DOMAIN_1. 2 hits.
PS50023. LIM_DOMAIN_2. 2 hits.
[Graphical view]

Sequences (2)i

Sequence statusi: Complete.

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

Isoform 1 (identifier: P50461-1) [UniParc]FASTAAdd to basket
Also known as: MLP-a

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
MPNWGGGAKC GACEKTVYHA EEIQCNGRSF HKTCFHCMAC RKALDSTTVA
60 70 80 90 100
AHESEIYCKV CYGRRYGPKG IGYGQGAGCL STDTGEHLGL QFQQSPKPAR
110 120 130 140 150
SVTTSNPSKF TAKFGESEKC PRCGKSVYAA EKVMGGGKPW HKTCFRCAIC
160 170 180 190
GKSLESTNVT DKDGELYCKV CYAKNFGPTG IGFGGLTQQV EKKE
Length:194
Mass (Da):20,969
Last modified:October 1, 1996 - v1
Checksum:iFDB6E4F8D258C35F
GO
Isoform 2 (identifier: P50461-2) [UniParc]FASTAAdd to basket
Also known as: MLP-b

The sequence of this isoform differs from the canonical sequence as follows:
     38-59: MACRKALDSTTVAAHESEIYCK → TLAQDLFPLCHLWEESGVHKC
     60-194: Missing.

Show »
Length:58
Mass (Da):6,510
Checksum:i582D53C0057BFE66
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti26N → H in AAF28868 (Ref. 4) Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_0154014W → R in CMD1M; unknown pathological significance; decreases interaction with TCAP. 2 PublicationsCorresponds to variant rs45550635dbSNPEnsembl.1
Natural variantiVAR_04593244L → P in CMH12; decreases PKC/PRKCA activity. 2 PublicationsCorresponds to variant rs104894205dbSNPEnsembl.1
Natural variantiVAR_04593354 – 55SE → RG in CMH12; decreases PKC/PRKCA activity. 1 PublicationCorresponds to variant rs281865416dbSNPEnsembl.2
Natural variantiVAR_04593458C → G in CMH12; decreases interaction with NRAP and ACTN2, decreases zinc-binding and impairs protein stability, decreases PKC/PRKCA activity. 3 PublicationsCorresponds to variant rs104894204dbSNPEnsembl.1
Natural variantiVAR_07680572G → R in CMD1M; unknown pathological significance; increases PKC/PRKCA activity. 2 Publications1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_05857538 – 59MACRK…EIYCK → TLAQDLFPLCHLWEESGVHK C in isoform 2. Add BLAST22
Alternative sequenceiVSP_05857660 – 194Missing in isoform 2. Add BLAST135

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U20324 mRNA. Translation: AAA91104.1.
U49837 mRNA. Translation: AAA92571.1.
U72898
, U72894, U72895, U72896, U72897 Genomic DNA. Translation: AAD00189.1.
U72899 mRNA. Translation: AAD00183.1.
AF121260 mRNA. Translation: AAF28868.1.
JN898958 mRNA. Translation: AFH66949.1.
BC005900 mRNA. Translation: AAH05900.1.
BC024010 mRNA. Translation: AAH24010.1.
BC057221 mRNA. Translation: AAH57221.1.
CCDSiCCDS7848.1. [P50461-1]
RefSeqiNP_003467.1. NM_003476.4.
UniGeneiHs.83577.

Genome annotation databases

EnsembliENST00000265968; ENSP00000265968; ENSG00000129170. [P50461-1]
ENST00000533783; ENSP00000431813; ENSG00000129170. [P50461-1]
GeneIDi8048.
KEGGihsa:8048.
UCSCiuc001mpk.4. human. [P50461-1]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
U20324 mRNA. Translation: AAA91104.1.
U49837 mRNA. Translation: AAA92571.1.
U72898
, U72894, U72895, U72896, U72897 Genomic DNA. Translation: AAD00189.1.
U72899 mRNA. Translation: AAD00183.1.
AF121260 mRNA. Translation: AAF28868.1.
JN898958 mRNA. Translation: AFH66949.1.
BC005900 mRNA. Translation: AAH05900.1.
BC024010 mRNA. Translation: AAH24010.1.
BC057221 mRNA. Translation: AAH57221.1.
CCDSiCCDS7848.1. [P50461-1]
RefSeqiNP_003467.1. NM_003476.4.
UniGeneiHs.83577.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
2O10NMR-A7-66[»]
2O13NMR-A119-176[»]
ProteinModelPortaliP50461.
SMRiP50461.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi113736. 7 interactors.
IntActiP50461. 10 interactors.
STRINGi9606.ENSP00000265968.

PTM databases

iPTMnetiP50461.
PhosphoSitePlusiP50461.

Polymorphism and mutation databases

BioMutaiCSRP3.
DMDMi1705933.

Proteomic databases

EPDiP50461.
MaxQBiP50461.
PaxDbiP50461.
PeptideAtlasiP50461.
PRIDEiP50461.

Protocols and materials databases

DNASUi8048.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000265968; ENSP00000265968; ENSG00000129170. [P50461-1]
ENST00000533783; ENSP00000431813; ENSG00000129170. [P50461-1]
GeneIDi8048.
KEGGihsa:8048.
UCSCiuc001mpk.4. human. [P50461-1]

Organism-specific databases

CTDi8048.
DisGeNETi8048.
GeneCardsiCSRP3.
GeneReviewsiCSRP3.
HGNCiHGNC:2472. CSRP3.
HPAiHPA042581.
MalaCardsiCSRP3.
MIMi600824. gene.
607482. phenotype.
612124. phenotype.
neXtProtiNX_P50461.
OpenTargetsiENSG00000129170.
Orphaneti154. Familial isolated dilated cardiomyopathy.
155. Familial isolated hypertrophic cardiomyopathy.
PharmGKBiPA26971.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410ITI8. Eukaryota.
ENOG410Z840. LUCA.
GeneTreeiENSGT00550000074548.
HOGENOMiHOG000111233.
HOVERGENiHBG051143.
InParanoidiP50461.
KOiK09377.
OMAiQSPKQAR.
OrthoDBiEOG091G11RX.
PhylomeDBiP50461.
TreeFamiTF313758.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000129170-MONOMER.
SIGNORiP50461.

Miscellaneous databases

EvolutionaryTraceiP50461.
GeneWikiiCSRP3.
GenomeRNAii8048.
PROiP50461.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000129170.
CleanExiHS_CSRP3.
ExpressionAtlasiP50461. baseline and differential.
GenevisibleiP50461. HS.

Family and domain databases

Gene3Di2.10.110.10. 2 hits.
InterProiIPR001781. Znf_LIM.
[Graphical view]
PfamiPF00412. LIM. 2 hits.
[Graphical view]
SMARTiSM00132. LIM. 2 hits.
[Graphical view]
PROSITEiPS00478. LIM_DOMAIN_1. 2 hits.
PS50023. LIM_DOMAIN_2. 2 hits.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCSRP3_HUMAN
AccessioniPrimary (citable) accession number: P50461
Secondary accession number(s): Q9P131, S4S7M7
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 1, 1996
Last sequence update: October 1, 1996
Last modified: November 30, 2016
This is version 159 of the entry and version 1 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

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 11
    Human chromosome 11: 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. 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.