ID   CCG2_HUMAN              Reviewed;         323 AA.
AC   Q9Y698; Q2M1M1; Q5TGT3; Q9UGZ7;
DT   30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1999, sequence version 1.
DT   24-JAN-2024, entry version 185.
DE   RecName: Full=Voltage-dependent calcium channel gamma-2 subunit;
DE   AltName: Full=Neuronal voltage-gated calcium channel gamma-2 subunit;
DE   AltName: Full=Transmembrane AMPAR regulatory protein gamma-2;
DE            Short=TARP gamma-2;
GN   Name=CACNG2;
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 [MRNA].
RC   TISSUE=Cerebellum;
RX   PubMed=10221464; DOI=10.4065/74.4.357;
RA   Black J.L. III, Lennon V.A.;
RT   "Identification and cloning of putative human neuronal voltage-gated
RT   calcium channel gamma-2 and gamma-3 subunits: neurologic implications.";
RL   Mayo Clin. Proc. 74:357-361(1999).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RX   PubMed=15461802; DOI=10.1186/gb-2004-5-10-r84;
RA   Collins J.E., Wright C.L., Edwards C.A., Davis M.P., Grinham J.A.,
RA   Cole C.G., Goward M.E., Aguado B., Mallya M., Mokrab Y., Huckle E.J.,
RA   Beare D.M., Dunham I.;
RT   "A genome annotation-driven approach to cloning the human ORFeome.";
RL   Genome Biol. 5:R84.1-R84.11(2004).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=10591208; DOI=10.1038/990031;
RA   Dunham I., Hunt A.R., Collins J.E., Bruskiewich R., Beare D.M., Clamp M.,
RA   Smink L.J., Ainscough R., Almeida J.P., Babbage A.K., Bagguley C.,
RA   Bailey J., Barlow K.F., Bates K.N., Beasley O.P., Bird C.P., Blakey S.E.,
RA   Bridgeman A.M., Buck D., Burgess J., Burrill W.D., Burton J., Carder C.,
RA   Carter N.P., Chen Y., Clark G., Clegg S.M., Cobley V.E., Cole C.G.,
RA   Collier R.E., Connor R., Conroy D., Corby N.R., Coville G.J., Cox A.V.,
RA   Davis J., Dawson E., Dhami P.D., Dockree C., Dodsworth S.J., Durbin R.M.,
RA   Ellington A.G., Evans K.L., Fey J.M., Fleming K., French L., Garner A.A.,
RA   Gilbert J.G.R., Goward M.E., Grafham D.V., Griffiths M.N.D., Hall C.,
RA   Hall R.E., Hall-Tamlyn G., Heathcott R.W., Ho S., Holmes S., Hunt S.E.,
RA   Jones M.C., Kershaw J., Kimberley A.M., King A., Laird G.K., Langford C.F.,
RA   Leversha M.A., Lloyd C., Lloyd D.M., Martyn I.D., Mashreghi-Mohammadi M.,
RA   Matthews L.H., Mccann O.T., Mcclay J., Mclaren S., McMurray A.A.,
RA   Milne S.A., Mortimore B.J., Odell C.N., Pavitt R., Pearce A.V., Pearson D.,
RA   Phillimore B.J.C.T., Phillips S.H., Plumb R.W., Ramsay H., Ramsey Y.,
RA   Rogers L., Ross M.T., Scott C.E., Sehra H.K., Skuce C.D., Smalley S.,
RA   Smith M.L., Soderlund C., Spragon L., Steward C.A., Sulston J.E.,
RA   Swann R.M., Vaudin M., Wall M., Wallis J.M., Whiteley M.N., Willey D.L.,
RA   Williams L., Williams S.A., Williamson H., Wilmer T.E., Wilming L.,
RA   Wright C.L., Hubbard T., Bentley D.R., Beck S., Rogers J., Shimizu N.,
RA   Minoshima S., Kawasaki K., Sasaki T., Asakawa S., Kudoh J., Shintani A.,
RA   Shibuya K., Yoshizaki Y., Aoki N., Mitsuyama S., Roe B.A., Chen F., Chu L.,
RA   Crabtree J., Deschamps S., Do A., Do T., Dorman A., Fang F., Fu Y., Hu P.,
RA   Hua A., Kenton S., Lai H., Lao H.I., Lewis J., Lewis S., Lin S.-P., Loh P.,
RA   Malaj E., Nguyen T., Pan H., Phan S., Qi S., Qian Y., Ray L., Ren Q.,
RA   Shaull S., Sloan D., Song L., Wang Q., Wang Y., Wang Z., White J.,
RA   Willingham D., Wu H., Yao Z., Zhan M., Zhang G., Chissoe S., Murray J.,
RA   Miller N., Minx P., Fulton R., Johnson D., Bemis G., Bentley D.,
RA   Bradshaw H., Bourne S., Cordes M., Du Z., Fulton L., Goela D., Graves T.,
RA   Hawkins J., Hinds K., Kemp K., Latreille P., Layman D., Ozersky P.,
RA   Rohlfing T., Scheet P., Walker C., Wamsley A., Wohldmann P., Pepin K.,
RA   Nelson J., Korf I., Bedell J.A., Hillier L.W., Mardis E., Waterston R.,
RA   Wilson R., Emanuel B.S., Shaikh T., Kurahashi H., Saitta S., Budarf M.L.,
RA   McDermid H.E., Johnson A., Wong A.C.C., Morrow B.E., Edelmann L., Kim U.J.,
RA   Shizuya H., Simon M.I., Dumanski J.P., Peyrard M., Kedra D., Seroussi E.,
RA   Fransson I., Tapia I., Bruder C.E., O'Brien K.P., Wilkinson P.,
RA   Bodenteich A., Hartman K., Hu X., Khan A.S., Lane L., Tilahun Y.,
RA   Wright H.;
RT   "The DNA sequence of human chromosome 22.";
RL   Nature 402:489-495(1999).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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   [5]
RP   FUNCTION, AND INTERACTION WITH GRIA1.
RX   PubMed=20805473; DOI=10.1073/pnas.1011706107;
RA   Shi Y., Suh Y.H., Milstein A.D., Isozaki K., Schmid S.M., Roche K.W.,
RA   Nicoll R.A.;
RT   "Functional comparison of the effects of TARPs and cornichons on AMPA
RT   receptor trafficking and gating.";
RL   Proc. Natl. Acad. Sci. U.S.A. 107:16315-16319(2010).
RN   [6]
RP   STRUCTURE BY ELECTRON MICROSCOPY (3.90 ANGSTROMS) OF 2-208.
RX   PubMed=30122377; DOI=10.1016/j.neuron.2018.07.027;
RA   Twomey E.C., Yelshanskaya M.V., Vassilevski A.A., Sobolevsky A.I.;
RT   "Mechanisms of channel block in calcium-permeable AMPA receptors.";
RL   Neuron 99:956-968.e4(2018).
RN   [7]
RP   VARIANT MRD10 LEU-143, AND CHARACTERIZATION OF VARIANT MRD10 LEU-143.
RX   PubMed=21376300; DOI=10.1016/j.ajhg.2011.02.001;
RA   Hamdan F.F., Gauthier J., Araki Y., Lin D.T., Yoshizawa Y., Higashi K.,
RA   Park A.R., Spiegelman D., Dobrzeniecka S., Piton A., Tomitori H., Daoud H.,
RA   Massicotte C., Henrion E., Diallo O., Shekarabi M., Marineau C.,
RA   Shevell M., Maranda B., Mitchell G., Nadeau A., D'Anjou G., Vanasse M.,
RA   Srour M., Lafreniere R.G., Drapeau P., Lacaille J.C., Kim E., Lee J.R.,
RA   Igarashi K., Huganir R.L., Rouleau G.A., Michaud J.L.;
RT   "Excess of de novo deleterious mutations in genes associated with
RT   glutamatergic systems in nonsyndromic intellectual disability.";
RL   Am. J. Hum. Genet. 88:306-316(2011).
CC   -!- FUNCTION: Regulates the trafficking and gating properties of AMPA-
CC       selective glutamate receptors (AMPARs). Promotes their targeting to the
CC       cell membrane and synapses and modulates their gating properties by
CC       slowing their rates of activation, deactivation and desensitization.
CC       Does not show subunit-specific AMPA receptor regulation and regulates
CC       all AMPAR subunits. Thought to stabilize the calcium channel in an
CC       inactivated (closed) state. {ECO:0000269|PubMed:20805473}.
CC   -!- SUBUNIT: The L-type calcium channel is composed of five subunits:
CC       alpha-1, alpha-2/delta, beta and gamma. Interacts with the PDZ domains
CC       of DLG4/PSD-95 and DLG1/SAP97. May interact with GOPC (By similarity).
CC       Acts as an auxiliary subunit for AMPA-selective glutamate receptors
CC       (AMPARs). Found in a complex with GRIA1, GRIA2, GRIA3, GRIA4, CNIH2,
CC       CNIH3, CACNG3, CACNG4, CACNG5, CACNG7 and CACNG8 (By similarity).
CC       Interacts with GRIA1 and GRIA2 (PubMed:20805473). Interacts with MPP2
CC       (By similarity). {ECO:0000250|UniProtKB:Q71RJ2,
CC       ECO:0000269|PubMed:20805473}.
CC   -!- INTERACTION:
CC       Q9Y698; O43516-4: WIPF1; NbExp=3; IntAct=EBI-6659211, EBI-12052927;
CC   -!- SUBCELLULAR LOCATION: Membrane; Multi-pass membrane protein. Synapse,
CC       synaptosome {ECO:0000250|UniProtKB:Q71RJ2}.
CC   -!- TISSUE SPECIFICITY: Brain.
CC   -!- PTM: Phosphorylation of Thr-321 impairs interaction with DLG1 and DLG4.
CC   -!- DISEASE: Intellectual developmental disorder, autosomal dominant 10
CC       (MRD10) [MIM:614256]: A disorder characterized by significantly below
CC       average general intellectual functioning associated with impairments in
CC       adaptive behavior and manifested during the developmental period.
CC       {ECO:0000269|PubMed:21376300}. Note=The disease is caused by variants
CC       affecting the gene represented in this entry.
CC   -!- SIMILARITY: Belongs to the PMP-22/EMP/MP20 family. CACNG subfamily.
CC       {ECO:0000305}.
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DR   EMBL; AF096322; AAD22738.1; -; mRNA.
DR   EMBL; CR456414; CAG30300.1; -; mRNA.
DR   EMBL; AL022313; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL031845; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; AL049749; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; BC069612; AAH69612.1; -; mRNA.
DR   EMBL; BC112297; AAI12298.1; -; mRNA.
DR   EMBL; BC112299; AAI12300.1; -; mRNA.
DR   CCDS; CCDS13931.1; -.
DR   RefSeq; NP_006069.1; NM_006078.3.
DR   PDB; 6DLZ; EM; 3.90 A; A/B/C/D=2-208.
DR   PDB; 6DM0; EM; 4.40 A; A/B/C/D=2-208.
DR   PDB; 6DM1; EM; 4.20 A; A/B/C/D=2-208.
DR   PDB; 6O9G; EM; 4.80 A; A/B/C/D=2-208.
DR   PDB; 6TNO; X-ray; 1.90 A; B/D/F=225-232.
DR   PDBsum; 6DLZ; -.
DR   PDBsum; 6DM0; -.
DR   PDBsum; 6DM1; -.
DR   PDBsum; 6O9G; -.
DR   PDBsum; 6TNO; -.
DR   AlphaFoldDB; Q9Y698; -.
DR   EMDB; EMD-7959; -.
DR   EMDB; EMD-7960; -.
DR   EMDB; EMD-7961; -.
DR   SMR; Q9Y698; -.
DR   BioGRID; 115648; 27.
DR   CORUM; Q9Y698; -.
DR   DIP; DIP-48977N; -.
DR   IntAct; Q9Y698; 15.
DR   STRING; 9606.ENSP00000300105; -.
DR   BindingDB; Q9Y698; -.
DR   ChEMBL; CHEMBL4296111; -.
DR   DrugBank; DB13746; Bioallethrin.
DR   DrugBank; DB11148; Butamben.
DR   DrugBank; DB09235; Efonidipine.
DR   DrugBank; DB00228; Enflurane.
DR   DrugBank; DB00153; Ergocalciferol.
DR   DrugBank; DB00898; Ethanol.
DR   DrugBank; DB00622; Nicardipine.
DR   DrugBank; DB00421; Spironolactone.
DR   DrugBank; DB00661; Verapamil.
DR   TCDB; 8.A.16.2.1; the ca(+) channel auxiliary subunit Gama1-Gama8 (ccaGama) family.
DR   GlyCosmos; Q9Y698; 1 site, No reported glycans.
DR   GlyGen; Q9Y698; 2 sites, 1 O-linked glycan (1 site).
DR   iPTMnet; Q9Y698; -.
DR   PhosphoSitePlus; Q9Y698; -.
DR   BioMuta; CACNG2; -.
DR   DMDM; 6685289; -.
DR   MassIVE; Q9Y698; -.
DR   PaxDb; 9606-ENSP00000300105; -.
DR   PeptideAtlas; Q9Y698; -.
DR   ProteomicsDB; 86635; -.
DR   Antibodypedia; 25748; 251 antibodies from 36 providers.
DR   DNASU; 10369; -.
DR   Ensembl; ENST00000300105.7; ENSP00000300105.6; ENSG00000166862.7.
DR   GeneID; 10369; -.
DR   KEGG; hsa:10369; -.
DR   MANE-Select; ENST00000300105.7; ENSP00000300105.6; NM_006078.5; NP_006069.1.
DR   UCSC; uc003aps.3; human.
DR   AGR; HGNC:1406; -.
DR   CTD; 10369; -.
DR   DisGeNET; 10369; -.
DR   GeneCards; CACNG2; -.
DR   HGNC; HGNC:1406; CACNG2.
DR   HPA; ENSG00000166862; Tissue enriched (brain).
DR   MalaCards; CACNG2; -.
DR   MIM; 602911; gene.
DR   MIM; 614256; phenotype.
DR   neXtProt; NX_Q9Y698; -.
DR   OpenTargets; ENSG00000166862; -.
DR   Orphanet; 178469; Autosomal dominant non-syndromic intellectual disability.
DR   PharmGKB; PA26016; -.
DR   VEuPathDB; HostDB:ENSG00000166862; -.
DR   eggNOG; ENOG502QSNI; Eukaryota.
DR   GeneTree; ENSGT01050000244893; -.
DR   HOGENOM; CLU_053704_0_1_1; -.
DR   InParanoid; Q9Y698; -.
DR   OMA; CIQKESK; -.
DR   OrthoDB; 2957055at2759; -.
DR   PhylomeDB; Q9Y698; -.
DR   TreeFam; TF327980; -.
DR   PathwayCommons; Q9Y698; -.
DR   Reactome; R-HSA-112308; Presynaptic depolarization and calcium channel opening.
DR   Reactome; R-HSA-399719; Trafficking of AMPA receptors.
DR   Reactome; R-HSA-5682910; LGI-ADAM interactions.
DR   SignaLink; Q9Y698; -.
DR   SIGNOR; Q9Y698; -.
DR   BioGRID-ORCS; 10369; 24 hits in 1141 CRISPR screens.
DR   ChiTaRS; CACNG2; human.
DR   GeneWiki; CACNG2; -.
DR   GenomeRNAi; 10369; -.
DR   Pharos; Q9Y698; Tbio.
DR   PRO; PR:Q9Y698; -.
DR   Proteomes; UP000005640; Chromosome 22.
DR   RNAct; Q9Y698; Protein.
DR   Bgee; ENSG00000166862; Expressed in right hemisphere of cerebellum and 54 other cell types or tissues.
DR   GO; GO:0032281; C:AMPA glutamate receptor complex; ISS:UniProtKB.
DR   GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR   GO; GO:0044300; C:cerebellar mossy fiber; IEA:Ensembl.
DR   GO; GO:0030666; C:endocytic vesicle membrane; TAS:Reactome.
DR   GO; GO:0098978; C:glutamatergic synapse; IEA:Ensembl.
DR   GO; GO:0098686; C:hippocampal mossy fiber to CA3 synapse; IEA:Ensembl.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0098839; C:postsynaptic density membrane; IBA:GO_Central.
DR   GO; GO:0098685; C:Schaffer collateral - CA1 synapse; IEA:Ensembl.
DR   GO; GO:0036477; C:somatodendritic compartment; IEA:Ensembl.
DR   GO; GO:0005891; C:voltage-gated calcium channel complex; TAS:ProtInc.
DR   GO; GO:0016247; F:channel regulator activity; IBA:GO_Central.
DR   GO; GO:0035255; F:ionotropic glutamate receptor binding; IEA:Ensembl.
DR   GO; GO:0005245; F:voltage-gated calcium channel activity; IBA:GO_Central.
DR   GO; GO:0060082; P:eye blink reflex; IEA:Ensembl.
DR   GO; GO:0051899; P:membrane depolarization; IEA:Ensembl.
DR   GO; GO:0060081; P:membrane hyperpolarization; IEA:Ensembl.
DR   GO; GO:0007528; P:neuromuscular junction development; IEA:Ensembl.
DR   GO; GO:0099590; P:neurotransmitter receptor internalization; IBA:GO_Central.
DR   GO; GO:0099645; P:neurotransmitter receptor localization to postsynaptic specialization membrane; IEA:Ensembl.
DR   GO; GO:0098943; P:neurotransmitter receptor transport, postsynaptic endosome to lysosome; IBA:GO_Central.
DR   GO; GO:1904510; P:positive regulation of protein localization to basolateral plasma membrane; IEA:Ensembl.
DR   GO; GO:0051968; P:positive regulation of synaptic transmission, glutamatergic; IBA:GO_Central.
DR   GO; GO:0098970; P:postsynaptic neurotransmitter receptor diffusion trapping; IBA:GO_Central.
DR   GO; GO:0006612; P:protein targeting to membrane; IEA:Ensembl.
DR   GO; GO:2000311; P:regulation of AMPA receptor activity; ISS:UniProtKB.
DR   GO; GO:0051592; P:response to calcium ion; IEA:Ensembl.
DR   GO; GO:0019226; P:transmission of nerve impulse; IBA:GO_Central.
DR   Gene3D; 1.20.140.150; -; 1.
DR   InterPro; IPR004031; PMP22/EMP/MP20/Claudin.
DR   InterPro; IPR005422; VDCC_g2su.
DR   InterPro; IPR008368; VDCC_gsu.
DR   PANTHER; PTHR12107; VOLTAGE-DEPENDENT CALCIUM CHANNEL GAMMA SUBUNIT; 1.
DR   PANTHER; PTHR12107:SF1; VOLTAGE-DEPENDENT CALCIUM CHANNEL GAMMA-2 SUBUNIT; 1.
DR   Pfam; PF00822; PMP22_Claudin; 1.
DR   PRINTS; PR01792; VDCCGAMMA.
DR   PRINTS; PR01602; VDCCGAMMA2.
DR   Genevisible; Q9Y698; HS.
PE   1: Evidence at protein level;
KW   3D-structure; Calcium; Calcium channel; Calcium transport; Disease variant;
KW   Glycoprotein; Intellectual disability; Ion channel; Ion transport;
KW   Membrane; Phosphoprotein; Reference proteome; Synapse; Synaptosome;
KW   Transmembrane; Transmembrane helix; Transport; Voltage-gated channel.
FT   CHAIN           1..323
FT                   /note="Voltage-dependent calcium channel gamma-2 subunit"
FT                   /id="PRO_0000164673"
FT   TRANSMEM        10..30
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        104..124
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        134..154
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        182..202
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   REGION          233..261
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         253
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q71RJ2"
FT   MOD_RES         271
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:O88602"
FT   MOD_RES         321
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0000250|UniProtKB:O88602"
FT   CARBOHYD        48
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   VARIANT         143
FT                   /note="V -> L (in MRD10; significantly reduced ability to
FT                   bind GRIA1 or GRIA2 AMPARs; cell surface expression of
FT                   GRIA1 is reduced in transfected hippocampal neurons and
FT                   HEK293 cells producing mutant protein compared to cells
FT                   producing the wild-type)"
FT                   /evidence="ECO:0000269|PubMed:21376300"
FT                   /id="VAR_066599"
FT   STRAND          227..229
FT                   /evidence="ECO:0007829|PDB:6TNO"
SQ   SEQUENCE   323 AA;  35966 MW;  BF46A87E96B27934 CRC64;
     MGLFDRGVQM LLTTVGAFAA FSLMTIAVGT DYWLYSRGVC KTKSVSENET SKKNEEVMTH
     SGLWRTCCLE GNFKGLCKQI DHFPEDADYE ADTAEYFLRA VRASSIFPIL SVILLFMGGL
     CIAASEFYKT RHNIILSAGI FFVSAGLSNI IGIIVYISAN AGDPSKSDSK KNSYSYGWSF
     YFGALSFIIA EMVGVLAVHM FIDRHKQLRA TARATDYLQA SAITRIPSYR YRYQRRSRSS
     SRSTEPSHSR DASPVGIKGF NTLPSTEISM YTLSRDPLKA ATTPTATYNS DRDNSFLQVH
     NCIQKENKDS LHSNTANRRT TPV
//