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Protein

Cerebral cavernous malformations 2 protein

Gene

CCM2

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

Functioni

Component of the CCM signaling pathway which is a crucial regulator of heart and vessel formation and integrity. May act through the stabilization of endothelial cell junctions (By similarity). May function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major role in the modulation of MAP3K3-dependent p38 activation induced by hyperosmotic shock (By similarity).By similarity

GO - Biological processi

  • blood vessel endothelial cell differentiation Source: Ensembl
  • cell-cell junction organization Source: Ensembl
  • endothelial cell development Source: Ensembl
  • endothelial tube morphogenesis Source: MGI
  • inner ear development Source: Ensembl
  • integrin-mediated signaling pathway Source: UniProtKB
  • in utero embryonic development Source: Ensembl
  • multicellular organism growth Source: Ensembl
  • pericardium development Source: Ensembl
  • stress-activated MAPK cascade Source: UniProtKB
  • vasculogenesis Source: UniProtKB
  • venous blood vessel morphogenesis Source: Ensembl
Complete GO annotation...

Keywords - Molecular functioni

Developmental protein

Enzyme and pathway databases

BioCyciZFISH:ENSG00000136280-MONOMER.

Names & Taxonomyi

Protein namesi
Recommended name:
Cerebral cavernous malformations 2 protein
Alternative name(s):
Malcavernin1 Publication
Gene namesi
Name:CCM2
Synonyms:C7orf22
ORF Names:PP10187
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 7

Organism-specific databases

HGNCiHGNC:21708. CCM2.

Subcellular locationi

GO - Cellular componenti

  • cytoplasm Source: UniProtKB
  • protein complex Source: Ensembl
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm

Pathology & Biotechi

Involvement in diseasei

Cerebral cavernous malformations 2 (CCM2)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA congenital vascular anomaly of the central nervous system that can result in hemorrhagic stroke, seizures, recurrent headaches, and focal neurologic deficits. The lesions are characterized by grossly enlarged blood vessels consisting of a single layer of endothelium and without any intervening neural tissue, ranging in diameter from a few millimeters to several centimeters.
See also OMIM:603284
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_023577198L → R in CCM2. 1 PublicationCorresponds to variant rs137852843dbSNPEnsembl.1
Natural variantiVAR_067352215Q → H in CCM2; associated with Q-229. 1 Publication1
Natural variantiVAR_067353229L → Q in CCM2; associated with H-215. 1 Publication1

Keywords - Diseasei

Disease mutation

Organism-specific databases

DisGeNETi83605.
MalaCardsiCCM2.
MIMi603284. phenotype.
OpenTargetsiENSG00000136280.
Orphaneti221061. Hereditary cerebral cavernous malformation.
PharmGKBiPA26145.

Polymorphism and mutation databases

BioMutaiCCM2.
DMDMi74733042.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000894241 – 444Cerebral cavernous malformations 2 proteinAdd BLAST444

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei15PhosphoserineCombined sources1
Modified residuei164PhosphoserineCombined sources1
Modified residuei384PhosphoserineBy similarity1
Modified residuei393PhosphoserineBy similarity1
Modified residuei394PhosphothreonineBy similarity1
Modified residuei396PhosphoserineBy similarity1
Modified residuei399PhosphothreonineBy similarity1

Keywords - PTMi

Phosphoprotein

Proteomic databases

EPDiQ9BSQ5.
MaxQBiQ9BSQ5.
PaxDbiQ9BSQ5.
PeptideAtlasiQ9BSQ5.
PRIDEiQ9BSQ5.

PTM databases

iPTMnetiQ9BSQ5.
PhosphoSitePlusiQ9BSQ5.

Expressioni

Gene expression databases

BgeeiENSG00000136280.
CleanExiHS_CCM2.
ExpressionAtlasiQ9BSQ5. baseline and differential.
GenevisibleiQ9BSQ5. HS.

Organism-specific databases

HPAiHPA020273.
HPA021669.
HPA065815.

Interactioni

Subunit structurei

Part of a complex with MAP2K3, MAP3K3 and RAC1. Binds RAC1 directly and independently of its nucleotide-bound state (By similarity). Interacts with HEG1 and KRIT1; KRIT1 greatly facilitates the interaction with HEG1 (By similarity). Interacts with PDCD10.By similarity2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
DOK4Q8TEW63EBI-1573056,EBI-6918542
KRIT1O005224EBI-1573056,EBI-1573121
PDCD10Q9BUL85EBI-1573056,EBI-740195
TWIST2Q8WVJ93EBI-1573056,EBI-1797313
VSTM2LQ96N033EBI-1573056,EBI-948213

Protein-protein interaction databases

BioGridi123696. 14 interactors.
DIPiDIP-40609N.
IntActiQ9BSQ5. 11 interactors.
MINTiMINT-8404420.
STRINGi9606.ENSP00000370503.

Structurei

Secondary structure

1444
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Turni57 – 60Combined sources4
Beta strandi63 – 76Combined sources14
Helixi85 – 97Combined sources13
Beta strandi110 – 115Combined sources6
Beta strandi117 – 127Combined sources11
Beta strandi130 – 135Combined sources6
Helixi136 – 138Combined sources3
Beta strandi139 – 146Combined sources8
Beta strandi151 – 157Combined sources7
Beta strandi193 – 202Combined sources10
Helixi203 – 219Combined sources17
Helixi225 – 238Combined sources14
Helixi288 – 291Combined sources4
Helixi293 – 306Combined sources14
Turni307 – 309Combined sources3
Helixi312 – 326Combined sources15
Helixi331 – 342Combined sources12
Helixi344 – 356Combined sources13
Helixi359 – 371Combined sources13
Turni373 – 375Combined sources3
Helixi422 – 435Combined sources14

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4FQNX-ray1.90A/B/C/D283-379[»]
4TVQX-ray2.80E224-239[»]
4WJ7X-ray2.75A/B/C/D51-228[»]
4Y5OX-ray2.35A283-379[»]
4YKCX-ray2.70A290-444[»]
4YKDX-ray1.93A290-376[»]
4YL6X-ray2.10A290-376[»]
ProteinModelPortaliQ9BSQ5.
SMRiQ9BSQ5.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini59 – 248PIDPROSITE-ProRule annotationAdd BLAST190

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni283 – 376Harmonin homology domainAdd BLAST94

Domaini

The C-terminal region constitutes an independently folded domain that has structural similarity with the USH1C (harmonin) N-terminus, despite very low sequence similarity.1 Publication

Sequence similaritiesi

Belongs to the CCM2 family.Curated
Contains 1 PID domain.PROSITE-ProRule annotation

Phylogenomic databases

eggNOGiENOG410IHRT. Eukaryota.
ENOG410ZBNR. LUCA.
GeneTreeiENSGT00390000016168.
HOGENOMiHOG000231916.
HOVERGENiHBG054451.
InParanoidiQ9BSQ5.
OMAiGCSMDRD.
OrthoDBiEOG091G08B3.
PhylomeDBiQ9BSQ5.
TreeFamiTF328517.

Family and domain databases

CDDicd13516. HHD_CCM2. 1 hit.
Gene3Di2.30.29.30. 1 hit.
InterProiIPR032375. CCM2_C.
IPR026159. Malcavernin.
IPR011993. PH_dom-like.
IPR006020. PTB/PI_dom.
[Graphical view]
PANTHERiPTHR21642:SF4. PTHR21642:SF4. 1 hit.
PfamiPF16545. CCM2_C. 1 hit.
[Graphical view]
PROSITEiPS01179. PID. 1 hit.
[Graphical view]

Sequences (4)i

Sequence statusi: Complete.

This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform 1 (identifier: Q9BSQ5-1) [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
MEEEGKKGKK PGIVSPFKRV FLKGEKSRDK KAHEKVTERR PLHTVVLSLP
60 70 80 90 100
ERVEPDRLLS DYIEKEVKYL GQLTSIPGYL NPSSRTEILH FIDNAKRAHQ
110 120 130 140 150
LPGHLTQEHD AVLSLSAYNV KLAWRDGEDI ILRVPIHDIA AVSYVRDDAA
160 170 180 190 200
HLVVLKTAQD PGISPSQSLC AESSRGLSAG SLSESAVGPV EACCLVILAA
210 220 230 240 250
ESKVAAEELC CLLGQVFQVV YTESTIDFLD RAIFDGASTP THHLSLHSDD
260 270 280 290 300
SSTKVDIKET YEVEASTFCF PESVDVGGAS PHSKTISESE LSASATELLQ
310 320 330 340 350
DYMLTLRTKL SSQEIQQFAA LLHEYRNGAS IHEFCINLRQ LYGDSRKFLL
360 370 380 390 400
LGLRPFIPEK DSQHFENFLE TIGVKDGRGI ITDSFGRHRR ALSTTSSSTT
410 420 430 440
NGNRATGSSD DRSAPSEGDE WDRMISDISS DIEALGCSMD QDSA
Length:444
Mass (Da):48,837
Last modified:June 1, 2001 - v1
Checksum:i43F9C153B4DE460E
GO
Isoform 2 (identifier: Q9BSQ5-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     1-10: MEEEGKKGKK → MHSSCRQRRNQNLSKEIPQTEFHTGYSMENE

Show »
Length:465
Mass (Da):51,413
Checksum:iDA0E03C39B7DABE3
GO
Isoform 3 (identifier: Q9BSQ5-3) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     158-248: Missing.

Note: Gene prediction based on EST data.
Show »
Length:353
Mass (Da):39,460
Checksum:iDC6158E93D3376CE
GO
Isoform 4 (identifier: Q9BSQ5-4) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     11-68: Missing.

Note: Gene prediction based on EST data.
Show »
Length:386
Mass (Da):42,073
Checksum:iF1BA46DBF72FF047
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti268F → C in BAG53562 (PubMed:14702039).Curated1
Sequence conflicti440D → A in AAQ15228 (PubMed:15498874).Curated1
Sequence conflicti444A → ALWTVDGGAPTPSAQLS in AAQ15228 (PubMed:15498874).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_02357553V → I.1 PublicationCorresponds to variant rs2107732dbSNPEnsembl.1
Natural variantiVAR_023576120V → I.1 PublicationCorresponds to variant rs11552377dbSNPEnsembl.1
Natural variantiVAR_023577198L → R in CCM2. 1 PublicationCorresponds to variant rs137852843dbSNPEnsembl.1
Natural variantiVAR_067352215Q → H in CCM2; associated with Q-229. 1 Publication1
Natural variantiVAR_067353229L → Q in CCM2; associated with H-215. 1 Publication1
Natural variantiVAR_050768289S → N.Corresponds to variant rs2289366dbSNPEnsembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0244021 – 10MEEEGKKGKK → MHSSCRQRRNQNLSKEIPQT EFHTGYSMENE in isoform 2. 1 Publication10
Alternative sequenceiVSP_04669511 – 68Missing in isoform 4. CuratedAdd BLAST58
Alternative sequenceiVSP_046696158 – 248Missing in isoform 3. CuratedAdd BLAST91

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK098005 mRNA. Translation: BAG53562.1.
AF370392 mRNA. Translation: AAQ15228.1.
AC004847 Genomic DNA. No translation available.
AC013416 Genomic DNA. No translation available.
CH236960 Genomic DNA. Translation: EAL23746.1.
CH471128 Genomic DNA. Translation: EAW61061.1.
CH471128 Genomic DNA. Translation: EAW61064.1.
BC004903 mRNA. Translation: AAH04903.1.
BC008859 mRNA. Translation: AAH08859.1.
BC016832 mRNA. Translation: AAH16832.1.
BC025958 mRNA. Translation: AAH25958.1.
CCDSiCCDS34630.1. [Q9BSQ5-2]
CCDS5500.1. [Q9BSQ5-1]
CCDS55108.1. [Q9BSQ5-3]
CCDS55109.1. [Q9BSQ5-4]
RefSeqiNP_001025006.1. NM_001029835.2. [Q9BSQ5-2]
NP_001161406.1. NM_001167934.1. [Q9BSQ5-4]
NP_001161407.1. NM_001167935.1. [Q9BSQ5-3]
NP_113631.1. NM_031443.3. [Q9BSQ5-1]
UniGeneiHs.148272.

Genome annotation databases

EnsembliENST00000258781; ENSP00000258781; ENSG00000136280. [Q9BSQ5-1]
ENST00000381112; ENSP00000370503; ENSG00000136280. [Q9BSQ5-2]
ENST00000541586; ENSP00000444725; ENSG00000136280. [Q9BSQ5-4]
ENST00000544363; ENSP00000438035; ENSG00000136280. [Q9BSQ5-3]
GeneIDi83605.
KEGGihsa:83605.
UCSCiuc003tmo.4. human. [Q9BSQ5-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AK098005 mRNA. Translation: BAG53562.1.
AF370392 mRNA. Translation: AAQ15228.1.
AC004847 Genomic DNA. No translation available.
AC013416 Genomic DNA. No translation available.
CH236960 Genomic DNA. Translation: EAL23746.1.
CH471128 Genomic DNA. Translation: EAW61061.1.
CH471128 Genomic DNA. Translation: EAW61064.1.
BC004903 mRNA. Translation: AAH04903.1.
BC008859 mRNA. Translation: AAH08859.1.
BC016832 mRNA. Translation: AAH16832.1.
BC025958 mRNA. Translation: AAH25958.1.
CCDSiCCDS34630.1. [Q9BSQ5-2]
CCDS5500.1. [Q9BSQ5-1]
CCDS55108.1. [Q9BSQ5-3]
CCDS55109.1. [Q9BSQ5-4]
RefSeqiNP_001025006.1. NM_001029835.2. [Q9BSQ5-2]
NP_001161406.1. NM_001167934.1. [Q9BSQ5-4]
NP_001161407.1. NM_001167935.1. [Q9BSQ5-3]
NP_113631.1. NM_031443.3. [Q9BSQ5-1]
UniGeneiHs.148272.

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4FQNX-ray1.90A/B/C/D283-379[»]
4TVQX-ray2.80E224-239[»]
4WJ7X-ray2.75A/B/C/D51-228[»]
4Y5OX-ray2.35A283-379[»]
4YKCX-ray2.70A290-444[»]
4YKDX-ray1.93A290-376[»]
4YL6X-ray2.10A290-376[»]
ProteinModelPortaliQ9BSQ5.
SMRiQ9BSQ5.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi123696. 14 interactors.
DIPiDIP-40609N.
IntActiQ9BSQ5. 11 interactors.
MINTiMINT-8404420.
STRINGi9606.ENSP00000370503.

PTM databases

iPTMnetiQ9BSQ5.
PhosphoSitePlusiQ9BSQ5.

Polymorphism and mutation databases

BioMutaiCCM2.
DMDMi74733042.

Proteomic databases

EPDiQ9BSQ5.
MaxQBiQ9BSQ5.
PaxDbiQ9BSQ5.
PeptideAtlasiQ9BSQ5.
PRIDEiQ9BSQ5.

Protocols and materials databases

DNASUi83605.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000258781; ENSP00000258781; ENSG00000136280. [Q9BSQ5-1]
ENST00000381112; ENSP00000370503; ENSG00000136280. [Q9BSQ5-2]
ENST00000541586; ENSP00000444725; ENSG00000136280. [Q9BSQ5-4]
ENST00000544363; ENSP00000438035; ENSG00000136280. [Q9BSQ5-3]
GeneIDi83605.
KEGGihsa:83605.
UCSCiuc003tmo.4. human. [Q9BSQ5-1]

Organism-specific databases

CTDi83605.
DisGeNETi83605.
GeneCardsiCCM2.
GeneReviewsiCCM2.
HGNCiHGNC:21708. CCM2.
HPAiHPA020273.
HPA021669.
HPA065815.
MalaCardsiCCM2.
MIMi603284. phenotype.
607929. gene.
neXtProtiNX_Q9BSQ5.
OpenTargetsiENSG00000136280.
Orphaneti221061. Hereditary cerebral cavernous malformation.
PharmGKBiPA26145.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410IHRT. Eukaryota.
ENOG410ZBNR. LUCA.
GeneTreeiENSGT00390000016168.
HOGENOMiHOG000231916.
HOVERGENiHBG054451.
InParanoidiQ9BSQ5.
OMAiGCSMDRD.
OrthoDBiEOG091G08B3.
PhylomeDBiQ9BSQ5.
TreeFamiTF328517.

Enzyme and pathway databases

BioCyciZFISH:ENSG00000136280-MONOMER.

Miscellaneous databases

GeneWikiiCCM2.
GenomeRNAii83605.
PROiQ9BSQ5.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000136280.
CleanExiHS_CCM2.
ExpressionAtlasiQ9BSQ5. baseline and differential.
GenevisibleiQ9BSQ5. HS.

Family and domain databases

CDDicd13516. HHD_CCM2. 1 hit.
Gene3Di2.30.29.30. 1 hit.
InterProiIPR032375. CCM2_C.
IPR026159. Malcavernin.
IPR011993. PH_dom-like.
IPR006020. PTB/PI_dom.
[Graphical view]
PANTHERiPTHR21642:SF4. PTHR21642:SF4. 1 hit.
PfamiPF16545. CCM2_C. 1 hit.
[Graphical view]
PROSITEiPS01179. PID. 1 hit.
[Graphical view]
ProtoNetiSearch...

Entry informationi

Entry nameiCCM2_HUMAN
AccessioniPrimary (citable) accession number: Q9BSQ5
Secondary accession number(s): A4D2L4
, B3KUV0, D3DVL4, E9PDJ3, F5H0E1, F5H551, Q71RE5, Q8TAT4
Entry historyi
Integrated into UniProtKB/Swiss-Prot: October 11, 2005
Last sequence update: June 1, 2001
Last modified: November 30, 2016
This is version 131 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, Direct protein sequencing, Reference proteome

Documents

  1. Human chromosome 7
    Human chromosome 7: 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.