ID CCM2_HUMAN Reviewed; 444 AA. AC Q9BSQ5; A4D2L4; B3KUV0; D3DVL4; E9PDJ3; F5H0E1; F5H551; Q71RE5; Q8TAT4; DT 11-OCT-2005, integrated into UniProtKB/Swiss-Prot. DT 01-JUN-2001, sequence version 1. DT 27-MAR-2024, entry version 175. DE RecName: Full=Cerebral cavernous malformations 2 protein; DE AltName: Full=Malcavernin {ECO:0000303|PubMed:12853948}; GN Name=CCM2; Synonyms=C7orf22; ORFNames=PP10187; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Thymus; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RX PubMed=15498874; DOI=10.1073/pnas.0404089101; RA Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H., Qiu X., RA Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y., Shu H., Chen X., RA Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S., Gu J.; RT "Large-scale cDNA transfection screening for genes related to cancer RT development and progression."; RL Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004). RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12853948; DOI=10.1038/nature01782; RA Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H., RA Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K., RA Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A., RA Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H., RA Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A., RA Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P., RA Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M., RA Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S., RA Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R., RA Strowmatt C., Latreille P., Miller N., Johnson D., Murray J., RA Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W., RA Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A., RA Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E., RA Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E., RA Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A., RA Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A., RA Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R., RA McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H., RA Wilson R.K.; RT "The DNA sequence of human chromosome 7."; RL Nature 424:157-164(2003). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12690205; DOI=10.1126/science.1083423; RA Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K., RA Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R., RA Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A., RA Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D., RA Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S., RA Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R., RA Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N., RA Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E., RA Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R., RA Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T., RA Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W., RA Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A., RA Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X., RA Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E., RA Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H., RA Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J., RA Adams M.D., Tsui L.-C.; RT "Human chromosome 7: DNA sequence and biology."; RL Science 300:767-772(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Brain, and Kidney; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP INVOLVEMENT IN CCM2. RX PubMed=14624391; DOI=10.1086/380314; RA Liquori C.L., Berg M.J., Siegel A.M., Huang E., Zawistowski J.S., RA Stoffer T., Verlaan D., Balogun F., Hughes L., Leedom T.P., Plummer N.W., RA Cannella M., Maglione V., Squitieri F., Johnson E.W., Rouleau G.A., RA Ptacek L., Marchuk D.A.; RT "Mutations in a gene encoding a novel protein containing a phosphotyrosine- RT binding domain cause type 2 cerebral cavernous malformations."; RL Am. J. Hum. Genet. 73:1459-1464(2003). RN [8] RP INTERACTION WITH PDCD10. RX PubMed=20489202; DOI=10.1074/jbc.m110.128470; RA Li X., Zhang R., Zhang H., He Y., Ji W., Min W., Boggon T.J.; RT "Crystal structure of CCM3, a cerebral cavernous malformation protein RT critical for vascular integrity."; RL J. Biol. Chem. 285:24099-24107(2010). RN [9] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-15, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Erythroleukemia; RX PubMed=23186163; DOI=10.1021/pr300630k; RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J., RA Mohammed S.; RT "Toward a comprehensive characterization of a human cancer cell RT phosphoproteome."; RL J. Proteome Res. 12:260-271(2013). RN [10] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-164, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [11] RP X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 283-379, PARTIAL PROTEIN SEQUENCE, RP DOMAIN, AND INTERACTION WITH PDCD10. RX PubMed=23266514; DOI=10.1016/j.febslet.2012.12.011; RA Fisher O.S., Zhang R., Li X., Murphy J.W., Demeler B., Boggon T.J.; RT "Structural studies of cerebral cavernous malformations 2 (CCM2) reveal a RT folded helical domain at its C-terminus."; RL FEBS Lett. 587:272-277(2013). RN [12] RP VARIANT CCM2 ARG-198, AND VARIANTS ILE-53 AND ILE-120. RX PubMed=14740320; DOI=10.1086/381718; RA Denier C., Goutagny S., Labauge P., Krivosic V., Arnoult M., Cousin A., RA Benabid A.L., Comoy J., Frerebeau P., Gilbert B., Houtteville J.P., Jan M., RA Lapierre F., Loiseau H., Menei P., Mercier P., Moreau J.J., RA Nivelon-Chevallier A., Parker F., Redondo A.M., Scarabin J.M., RA Tremoulet M., Zerah M., Maciazek J., Tournier-Lasserve E.; RT "Mutations within the MGC4607 gene cause cerebral cavernous RT malformations."; RL Am. J. Hum. Genet. 74:326-337(2004). RN [13] RP VARIANTS CCM2 HIS-215 AND GLN-229. RX PubMed=22415356; DOI=10.1007/s12031-012-9741-5; RA Mosca L., Pileggi S., Avemaria F., Tarlarini C., Cigoli M.S., Capra V., RA De Marco P., Pavanello M., Marocchi A., Penco S.; RT "De Novo MGC4607 gene heterozygous missense variants in a child with RT multiple cerebral cavernous malformations."; RL J. Mol. Neurosci. 47:475-480(2012). 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 (By similarity). May CC function as a scaffold protein for MAP2K3-MAP3K3 signaling. Seems to CC play a major role in the modulation of MAP3K3-dependent p38 activation CC induced by hyperosmotic shock (By similarity). {ECO:0000250}. 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 (By similarity). Interacts with PDCD10. CC {ECO:0000250, ECO:0000269|PubMed:20489202, CC ECO:0000269|PubMed:23266514}. CC -!- INTERACTION: CC Q9BSQ5; Q8TEW6: DOK4; NbExp=3; IntAct=EBI-1573056, EBI-6918542; CC Q9BSQ5; P31273: HOXC8; NbExp=3; IntAct=EBI-1573056, EBI-1752118; CC Q9BSQ5; O00522: KRIT1; NbExp=15; IntAct=EBI-1573056, EBI-1573121; CC Q9BSQ5; Q9BUL8: PDCD10; NbExp=5; IntAct=EBI-1573056, EBI-740195; CC Q9BSQ5; Q13671: RIN1; NbExp=3; IntAct=EBI-1573056, EBI-366017; CC Q9BSQ5; Q9H1K6: TLNRD1; NbExp=3; IntAct=EBI-1573056, EBI-12344941; CC Q9BSQ5; Q8WVJ9: TWIST2; NbExp=3; IntAct=EBI-1573056, EBI-1797313; CC Q9BSQ5; Q96N03: VSTM2L; NbExp=3; IntAct=EBI-1573056, EBI-948213; CC Q9BSQ5-1; O00522: KRIT1; NbExp=2; IntAct=EBI-16157769, EBI-1573121; CC Q9BSQ5-1; Q99759: MAP3K3; NbExp=6; IntAct=EBI-16157769, EBI-307281; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; CC IsoId=Q9BSQ5-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9BSQ5-2; Sequence=VSP_024402; CC Name=3; CC IsoId=Q9BSQ5-3; Sequence=VSP_046696; CC Name=4; CC IsoId=Q9BSQ5-4; Sequence=VSP_046695; 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. CC {ECO:0000269|PubMed:23266514}. CC -!- DISEASE: Cerebral cavernous malformations 2 (CCM2) [MIM:603284]: A form CC of cerebral cavernous malformations, a congenital vascular anomaly of CC the central nervous system that can result in hemorrhagic stroke, CC seizures, recurrent headaches, and focal neurologic deficits. The CC lesions are characterized by grossly enlarged blood vessels consisting CC of a single layer of endothelium and without any intervening neural CC tissue, ranging in diameter from a few millimeters to several CC centimeters. CCM2 inheritance is autosomal dominant. CC {ECO:0000269|PubMed:14624391, ECO:0000269|PubMed:14740320, CC ECO:0000269|PubMed:22415356}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the CCM2 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; AK098005; BAG53562.1; -; mRNA. DR EMBL; AF370392; AAQ15228.1; -; mRNA. DR EMBL; AC004847; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AC013416; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH236960; EAL23746.1; -; Genomic_DNA. DR EMBL; CH471128; EAW61061.1; -; Genomic_DNA. DR EMBL; CH471128; EAW61064.1; -; Genomic_DNA. DR EMBL; BC004903; AAH04903.1; -; mRNA. DR EMBL; BC008859; AAH08859.1; -; mRNA. DR EMBL; BC016832; AAH16832.1; -; mRNA. DR EMBL; BC025958; AAH25958.1; -; mRNA. DR CCDS; CCDS34630.1; -. [Q9BSQ5-2] DR CCDS; CCDS5500.1; -. [Q9BSQ5-1] DR CCDS; CCDS55108.1; -. [Q9BSQ5-3] DR CCDS; CCDS55109.1; -. [Q9BSQ5-4] DR RefSeq; NP_001025006.1; NM_001029835.2. [Q9BSQ5-2] DR RefSeq; NP_001161406.1; NM_001167934.1. [Q9BSQ5-4] DR RefSeq; NP_001161407.1; NM_001167935.1. [Q9BSQ5-3] DR RefSeq; NP_113631.1; NM_031443.3. [Q9BSQ5-1] DR PDB; 4FQN; X-ray; 1.90 A; A/B/C/D=283-379. DR PDB; 4TVQ; X-ray; 2.80 A; E=224-239. DR PDB; 4WJ7; X-ray; 2.75 A; A/B/C/D=51-228. DR PDB; 4Y5O; X-ray; 2.35 A; A=283-379. DR PDB; 4YKC; X-ray; 2.70 A; A=290-444. DR PDB; 4YKD; X-ray; 1.93 A; A=290-376. DR PDB; 4YL6; X-ray; 2.10 A; A=290-376. DR PDBsum; 4FQN; -. DR PDBsum; 4TVQ; -. DR PDBsum; 4WJ7; -. DR PDBsum; 4Y5O; -. DR PDBsum; 4YKC; -. DR PDBsum; 4YKD; -. DR PDBsum; 4YL6; -. DR AlphaFoldDB; Q9BSQ5; -. DR SMR; Q9BSQ5; -. DR BioGRID; 123696; 40. DR ComplexPortal; CPX-984; CCM endothelial permeability complex. DR CORUM; Q9BSQ5; -. DR DIP; DIP-40609N; -. DR IntAct; Q9BSQ5; 18. DR MINT; Q9BSQ5; -. DR STRING; 9606.ENSP00000370503; -. DR GlyCosmos; Q9BSQ5; 1 site, 1 glycan. DR GlyGen; Q9BSQ5; 2 sites, 1 O-linked glycan (2 sites). DR iPTMnet; Q9BSQ5; -. DR PhosphoSitePlus; Q9BSQ5; -. DR BioMuta; CCM2; -. DR DMDM; 74733042; -. DR EPD; Q9BSQ5; -. DR jPOST; Q9BSQ5; -. DR MassIVE; Q9BSQ5; -. DR MaxQB; Q9BSQ5; -. DR PaxDb; 9606-ENSP00000370503; -. DR PeptideAtlas; Q9BSQ5; -. DR ProteomicsDB; 19677; -. DR ProteomicsDB; 25314; -. DR ProteomicsDB; 26772; -. DR ProteomicsDB; 78919; -. [Q9BSQ5-1] DR ProteomicsDB; 78920; -. [Q9BSQ5-2] DR Pumba; Q9BSQ5; -. DR Antibodypedia; 13519; 405 antibodies from 30 providers. DR DNASU; 83605; -. DR Ensembl; ENST00000258781.11; ENSP00000258781.7; ENSG00000136280.17. [Q9BSQ5-1] DR Ensembl; ENST00000381112.7; ENSP00000370503.3; ENSG00000136280.17. [Q9BSQ5-2] DR Ensembl; ENST00000541586.5; ENSP00000444725.1; ENSG00000136280.17. [Q9BSQ5-4] DR Ensembl; ENST00000544363.5; ENSP00000438035.1; ENSG00000136280.17. [Q9BSQ5-3] DR GeneID; 83605; -. DR KEGG; hsa:83605; -. DR MANE-Select; ENST00000258781.11; ENSP00000258781.7; NM_031443.4; NP_113631.1. DR UCSC; uc003tmo.4; human. [Q9BSQ5-1] DR AGR; HGNC:21708; -. DR CTD; 83605; -. DR DisGeNET; 83605; -. DR GeneCards; CCM2; -. DR GeneReviews; CCM2; -. DR HGNC; HGNC:21708; CCM2. DR HPA; ENSG00000136280; Tissue enhanced (brain). DR MalaCards; CCM2; -. DR MIM; 603284; phenotype. DR MIM; 607929; gene. DR neXtProt; NX_Q9BSQ5; -. DR OpenTargets; ENSG00000136280; -. DR Orphanet; 221061; Familial cerebral cavernous malformation. DR PharmGKB; PA26145; -. DR VEuPathDB; HostDB:ENSG00000136280; -. DR eggNOG; ENOG502QSZM; Eukaryota. DR GeneTree; ENSGT00390000016168; -. DR InParanoid; Q9BSQ5; -. DR OMA; LKTXDSS; -. DR OrthoDB; 2956487at2759; -. DR PhylomeDB; Q9BSQ5; -. DR TreeFam; TF328517; -. DR PathwayCommons; Q9BSQ5; -. DR SignaLink; Q9BSQ5; -. DR SIGNOR; Q9BSQ5; -. DR BioGRID-ORCS; 83605; 27 hits in 1156 CRISPR screens. DR ChiTaRS; CCM2; human. DR GeneWiki; CCM2; -. DR GenomeRNAi; 83605; -. DR Pharos; Q9BSQ5; Tbio. DR PRO; PR:Q9BSQ5; -. DR Proteomes; UP000005640; Chromosome 7. DR RNAct; Q9BSQ5; Protein. DR Bgee; ENSG00000136280; Expressed in putamen and 172 other cell types or tissues. DR ExpressionAtlas; Q9BSQ5; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005739; C:mitochondrion; IDA:HPA. DR GO; GO:0032991; C:protein-containing complex; IEA:Ensembl. DR GO; GO:0060837; P:blood vessel endothelial cell differentiation; IEA:Ensembl. DR GO; GO:0045216; P:cell-cell junction organization; IEA:Ensembl. DR GO; GO:0001885; P:endothelial cell development; IEA:Ensembl. DR GO; GO:0061154; P:endothelial tube morphogenesis; IMP:MGI. DR GO; GO:0003158; P:endothelium development; NAS:ComplexPortal. DR GO; GO:0007507; P:heart development; IBA:GO_Central. DR GO; GO:0001701; P:in utero embryonic development; IEA:Ensembl. DR GO; GO:0048839; P:inner ear development; IEA:Ensembl. DR GO; GO:0007229; P:integrin-mediated signaling pathway; TAS:UniProtKB. DR GO; GO:0035264; P:multicellular organism growth; IEA:Ensembl. DR GO; GO:0060039; P:pericardium development; IEA:Ensembl. DR GO; GO:0045765; P:regulation of angiogenesis; NAS:ComplexPortal. DR GO; GO:0051403; P:stress-activated MAPK cascade; TAS:UniProtKB. DR GO; GO:0001570; P:vasculogenesis; IMP:UniProtKB. DR GO; GO:0048845; P:venous blood vessel morphogenesis; IEA:Ensembl. DR CDD; cd13516; HHD_CCM2; 1. DR CDD; cd13166; PTB_CCM2; 1. DR DisProt; DP02978; -. DR Gene3D; 1.20.1160.20; -; 1. DR Gene3D; 2.30.29.30; Pleckstrin-homology domain (PH domain)/Phosphotyrosine-binding domain (PTB); 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:SF4; CEREBRAL CAVERNOUS MALFORMATIONS 2 PROTEIN; 1. DR PANTHER; PTHR21642; CEREBRAL CAVERNOUS MALFORMATIONS PROTEIN 2 HOMOLOG; 1. DR Pfam; PF16545; CCM2_C; 1. DR PROSITE; PS01179; PID; 1. DR Genevisible; Q9BSQ5; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytoplasm; Developmental protein; KW Direct protein sequencing; Disease variant; Phosphoprotein; KW Reference proteome. FT CHAIN 1..444 FT /note="Cerebral cavernous malformations 2 protein" FT /id="PRO_0000089424" FT DOMAIN 59..248 FT /note="PID" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00148" FT REGION 1..37 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT REGION 283..376 FT /note="Harmonin homology domain" FT REGION 391..423 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 21..37 FT /note="Basic and acidic residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 391..412 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT MOD_RES 15 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:23186163" FT MOD_RES 164 FT /note="Phosphoserine" FT /evidence="ECO:0007744|PubMed:24275569" FT MOD_RES 384 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8K2Y9" FT MOD_RES 393 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8K2Y9" FT MOD_RES 394 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8K2Y9" FT MOD_RES 396 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q8K2Y9" FT MOD_RES 399 FT /note="Phosphothreonine" FT /evidence="ECO:0000250|UniProtKB:Q8K2Y9" FT VAR_SEQ 1..10 FT /note="MEEEGKKGKK -> MHSSCRQRRNQNLSKEIPQTEFHTGYSMENE (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_024402" FT VAR_SEQ 11..68 FT /note="Missing (in isoform 4)" FT /evidence="ECO:0000305" FT /id="VSP_046695" FT VAR_SEQ 158..248 FT /note="Missing (in isoform 3)" FT /evidence="ECO:0000305" FT /id="VSP_046696" FT VARIANT 53 FT /note="V -> I (in dbSNP:rs2107732)" FT /evidence="ECO:0000269|PubMed:14740320" FT /id="VAR_023575" FT VARIANT 120 FT /note="V -> I (in dbSNP:rs11552377)" FT /evidence="ECO:0000269|PubMed:14740320" FT /id="VAR_023576" FT VARIANT 198 FT /note="L -> R (in CCM2; dbSNP:rs137852843)" FT /evidence="ECO:0000269|PubMed:14740320" FT /id="VAR_023577" FT VARIANT 215 FT /note="Q -> H (in CCM2; associated in cis with Q-229)" FT /evidence="ECO:0000269|PubMed:22415356" FT /id="VAR_067352" FT VARIANT 229 FT /note="L -> Q (in CCM2; associated in cis with H-215)" FT /evidence="ECO:0000269|PubMed:22415356" FT /id="VAR_067353" FT VARIANT 289 FT /note="S -> N (in dbSNP:rs2289366)" FT /id="VAR_050768" FT CONFLICT 268 FT /note="F -> C (in Ref. 1; BAG53562)" FT /evidence="ECO:0000305" FT CONFLICT 440 FT /note="D -> A (in Ref. 2; AAQ15228)" FT /evidence="ECO:0000305" FT CONFLICT 444 FT /note="A -> ALWTVDGGAPTPSAQLS (in Ref. 2; AAQ15228)" FT /evidence="ECO:0000305" FT TURN 57..60 FT /evidence="ECO:0007829|PDB:4WJ7" FT STRAND 63..76 FT /evidence="ECO:0007829|PDB:4WJ7" FT HELIX 85..97 FT /evidence="ECO:0007829|PDB:4WJ7" FT STRAND 110..115 FT /evidence="ECO:0007829|PDB:4WJ7" FT STRAND 117..127 FT /evidence="ECO:0007829|PDB:4WJ7" FT STRAND 130..135 FT /evidence="ECO:0007829|PDB:4WJ7" FT HELIX 136..138 FT /evidence="ECO:0007829|PDB:4WJ7" FT STRAND 139..146 FT /evidence="ECO:0007829|PDB:4WJ7" FT STRAND 151..157 FT /evidence="ECO:0007829|PDB:4WJ7" FT STRAND 193..202 FT /evidence="ECO:0007829|PDB:4WJ7" FT HELIX 203..219 FT /evidence="ECO:0007829|PDB:4WJ7" FT HELIX 225..238 FT /evidence="ECO:0007829|PDB:4TVQ" FT HELIX 288..291 FT /evidence="ECO:0007829|PDB:4FQN" FT HELIX 293..306 FT /evidence="ECO:0007829|PDB:4FQN" FT TURN 307..309 FT /evidence="ECO:0007829|PDB:4FQN" FT HELIX 312..326 FT /evidence="ECO:0007829|PDB:4FQN" FT HELIX 331..342 FT /evidence="ECO:0007829|PDB:4FQN" FT HELIX 344..356 FT /evidence="ECO:0007829|PDB:4FQN" FT HELIX 359..371 FT /evidence="ECO:0007829|PDB:4FQN" FT TURN 373..375 FT /evidence="ECO:0007829|PDB:4YL6" FT HELIX 422..435 FT /evidence="ECO:0007829|PDB:4YKC" SQ SEQUENCE 444 AA; 48837 MW; 43F9C153B4DE460E CRC64; MEEEGKKGKK PGIVSPFKRV FLKGEKSRDK KAHEKVTERR PLHTVVLSLP ERVEPDRLLS DYIEKEVKYL GQLTSIPGYL NPSSRTEILH FIDNAKRAHQ LPGHLTQEHD AVLSLSAYNV KLAWRDGEDI ILRVPIHDIA AVSYVRDDAA HLVVLKTAQD PGISPSQSLC AESSRGLSAG SLSESAVGPV EACCLVILAA ESKVAAEELC CLLGQVFQVV YTESTIDFLD RAIFDGASTP THHLSLHSDD SSTKVDIKET YEVEASTFCF PESVDVGGAS PHSKTISESE LSASATELLQ DYMLTLRTKL SSQEIQQFAA LLHEYRNGAS IHEFCINLRQ LYGDSRKFLL LGLRPFIPEK DSQHFENFLE TIGVKDGRGI ITDSFGRHRR ALSTTSSSTT NGNRATGSSD DRSAPSEGDE WDRMISDISS DIEALGCSMD QDSA //