CCM2_DANRE
ID CCM2_DANRE Reviewed; 455 AA.
AC Q6DRP4; Q0Z802; Q568L2;
DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot.
DT 16-AUG-2004, sequence version 1.
DT 03-AUG-2022, entry version 108.
DE RecName: Full=Cerebral cavernous malformations protein 2 homolog;
DE AltName: Full=Malcavernin {ECO:0000250|UniProtKB:Q9BSQ5};
DE AltName: Full=Valentine;
GN Name=ccm2; Synonyms=vtn;
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), DEVELOPMENTAL STAGE, AND DISRUPTION
RP PHENOTYPE.
RX PubMed=16873582; DOI=10.1242/dev.02469;
RA Mably J.D., Chuang L.P., Serluca F.C., Mohideen M.-A.P.K., Chen J.-N.,
RA Fishman M.C.;
RT "santa and valentine pattern concentric growth of cardiac myocardium in the
RT zebrafish.";
RL Development 133:3139-3146(2006).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=15256591; DOI=10.1073/pnas.0403929101;
RA Amsterdam A., Nissen R.M., Sun Z., Swindell E.C., Farrington S.,
RA Hopkins N.;
RT "Identification of 315 genes essential for early zebrafish development.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:12792-12797(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Ovary;
RG NIH - Zebrafish Gene Collection (ZGC) project;
RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP FUNCTION, INTERACTION WITH HEG1 AND KRIT1, DEVELOPMENTAL STAGE, AND
RP MUTAGENESIS OF LEU-197.
RX PubMed=19151727; DOI=10.1038/nm.1918;
RA Kleaveland B., Zheng X., Liu J.J., Blum Y., Tung J.J., Zou Z.,
RA Sweeney S.M., Chen M., Guo L., Lu M.M., Zhou D., Kitajewski J.,
RA Affolter M., Ginsberg M.H., Kahn M.L.;
RT "Regulation of cardiovascular development and integrity by the heart of
RT glass-cerebral cavernous malformation protein pathway.";
RL Nat. Med. 15:169-176(2009).
CC -!- FUNCTION: Component of the CCM signaling pathway which is a crucial
CC regulator of heart and vessel formation and integrity. May act through
CC the stabilization of endothelial cell junctions. May also function as a
CC scaffold protein for MAP2K3-MAP3K3 signaling. Seems to play a major
CC role in the modulation of MAP3K3-dependent p38 activation induced by
CC hyperosmotic shock (By similarity). {ECO:0000250,
CC ECO:0000269|PubMed:19151727}.
CC -!- SUBUNIT: Part of a complex with MAP2K3, MAP3K3 and RAC1. Binds RAC1
CC directly and independently of its nucleotide-bound state (By
CC similarity). Interacts with HEG1 and KRIT1; KRIT1 greatly facilitates
CC the interaction with HEG1. {ECO:0000250, ECO:0000269|PubMed:19151727}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6DRP4-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6DRP4-2; Sequence=VSP_015804;
CC -!- DEVELOPMENTAL STAGE: Expressed in the ventricular zone of the brain at
CC 28 hours post fertilization (hpf) and, at lower levels, in the
CC posterior cardinal vein and in the posterior intermediate inner cell
CC mass. At 48 hpf, still detected in the vein. At 28 and 48 hpf,
CC expressed at low levels in a region near the dorsal aorta.
CC {ECO:0000269|PubMed:16873582, ECO:0000269|PubMed:19151727}.
CC -!- DOMAIN: The C-terminal region constitutes an independently folded
CC domain that has structural similarity with the USH1C (harmonin) N-
CC terminus, despite very low sequence similarity. {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: The heart chambers in mutant animals are huge,
CC constituted of a monolayered myocardium lined by endocardium.
CC {ECO:0000269|PubMed:16873582}.
CC -!- SIMILARITY: Belongs to the CCM2 family. {ECO:0000305}.
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DR EMBL; DQ677878; ABG29499.1; -; mRNA.
DR EMBL; AY648715; AAT68033.1; -; mRNA.
DR EMBL; BC092812; AAH92812.1; -; mRNA.
DR RefSeq; NP_001002315.1; NM_001002315.3. [Q6DRP4-1]
DR AlphaFoldDB; Q6DRP4; -.
DR SMR; Q6DRP4; -.
DR STRING; 7955.ENSDARP00000022543; -.
DR PaxDb; Q6DRP4; -.
DR Ensembl; ENSDART00000003834; ENSDARP00000022543; ENSDARG00000013705. [Q6DRP4-1]
DR GeneID; 436586; -.
DR KEGG; dre:436586; -.
DR CTD; 83605; -.
DR ZFIN; ZDB-GENE-040712-6; ccm2.
DR eggNOG; ENOG502QSZM; Eukaryota.
DR GeneTree; ENSGT00390000016168; -.
DR HOGENOM; CLU_034621_1_0_1; -.
DR InParanoid; Q6DRP4; -.
DR OMA; EPYETET; -.
DR OrthoDB; 1446057at2759; -.
DR PhylomeDB; Q6DRP4; -.
DR TreeFam; TF328517; -.
DR PRO; PR:Q6DRP4; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 20.
DR Bgee; ENSDARG00000013705; Expressed in granulocyte and 28 other tissues.
DR ExpressionAtlas; Q6DRP4; baseline.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0009948; P:anterior/posterior axis specification; IGI:ZFIN.
DR GO; GO:0007043; P:cell-cell junction assembly; IMP:ZFIN.
DR GO; GO:0060047; P:heart contraction; IGI:ZFIN.
DR GO; GO:0007507; P:heart development; IMP:ZFIN.
DR GO; GO:0001570; P:vasculogenesis; IMP:ZFIN.
DR CDD; cd13516; HHD_CCM2; 1.
DR Gene3D; 2.30.29.30; -; 1.
DR InterPro; IPR032375; CCM2_C.
DR InterPro; IPR026159; Malcavernin.
DR InterPro; IPR011993; PH-like_dom_sf.
DR InterPro; IPR006020; PTB/PI_dom.
DR PANTHER; PTHR21642; PTHR21642; 1.
DR Pfam; PF16545; CCM2_C; 1.
DR SMART; SM00462; PTB; 1.
DR PROSITE; PS01179; PID; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cytoplasm; Developmental protein; Reference proteome.
FT CHAIN 1..455
FT /note="Cerebral cavernous malformations protein 2 homolog"
FT /id="PRO_0000089423"
FT DOMAIN 60..247
FT /note="PID"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148"
FT REGION 272..299
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 292..385
FT /note="Harmonin homology domain"
FT REGION 399..432
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 399..419
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT VAR_SEQ 362..455
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_015804"
FT MUTAGEN 197
FT /note="L->R: Loss of function in heart development. Loss of
FT HEG-binding."
FT /evidence="ECO:0000269|PubMed:19151727"
FT CONFLICT 319
FT /note="L -> P (in Ref. 3; AAH92812)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 455 AA; 49827 MW; 463DE4DFD566071C CRC64;
MEEDVKKVKK PGIVSPFKRV FLKGEKGRDK KALEKSTERR ALHTFSLSLP DHRIDPDILL
NDYIEKEVKY LGQLTSVPGY LNPSSRTEVL QLIDNARKSH QLAGQLTSEQ DAVVSLSAYN
VKLVWRDGED IILRVPIHDI AAVSYIRDDS LHLVVLKTAQ EPGGSPCHST EMSKSPTLSS
LSESGAVLVE VCCLLVLAVD NKAAAEELCL LLSQVFQIVY TESTIDFLDR AIFDGATTPT
RHLSIYSEDS SSKVDVKDVF EAEASTFSFQ SSLEAGHSSS PSPTSAPASP QTKTASESEL
STTAAELLQD YMTTLRTKLS SKEIQQFATL LHEYRNGASI HEFCINLRQL YGDSRKFLLL
GLRPFIPEKD SQHFENFLET IGVKDGRGII TDSFGRYKRT TSSASDSTTN GNGAAGGSDE
GTATSEGDEW DRMISDISND IEALGSSMDQ DGVPS
