CASR_BOVIN
ID CASR_BOVIN Reviewed; 1085 AA.
AC P35384;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-1994, sequence version 1.
DT 03-AUG-2022, entry version 138.
DE RecName: Full=Extracellular calcium-sensing receptor;
DE Short=CaSR;
DE AltName: Full=Parathyroid cell calcium-sensing receptor {ECO:0000303|PubMed:8255296};
DE Short=BoPCaR1 {ECO:0000303|PubMed:8255296};
DE Short=PCaR1 {ECO:0000303|PubMed:8255296};
DE Flags: Precursor;
GN Name=CASR; Synonyms=GPRC2A, PCAR1 {ECO:0000303|PubMed:8255296};
OS Bos taurus (Bovine).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Ruminantia; Pecora; Bovidae;
OC Bovinae; Bos.
OX NCBI_TaxID=9913;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC TISSUE=Parathyroid;
RX PubMed=8255296; DOI=10.1038/366575a0;
RA Brown E.M., Gamba G., Riccardi D., Lombardi M., Butters R., Kifor O.,
RA Sun A., Hediger M.A., Lytton J., Hebert S.C.;
RT "Cloning and characterization of an extracellular Ca(2+)-sensing receptor
RT from bovine parathyroid.";
RL Nature 366:575-580(1993).
CC -!- FUNCTION: G-protein-coupled receptor that senses changes in the
CC extracellular concentration of calcium ions and plays a key role in
CC maintaining calcium homeostasis (PubMed:8255296). Senses fluctuations
CC in the circulating calcium concentration and modulates the production
CC of parathyroid hormone (PTH) in parathyroid glands (By similarity). The
CC activity of this receptor is mediated by a G-protein that activates a
CC phosphatidylinositol-calcium second messenger system (PubMed:8255296).
CC The G-protein-coupled receptor activity is activated by a co-agonist
CC mechanism: aromatic amino acids, such as Trp or Phe, act concertedly
CC with divalent cations, such as calcium or magnesium, to achieve full
CC receptor activation (By similarity). {ECO:0000250|UniProtKB:P41180,
CC ECO:0000250|UniProtKB:Q9QY96, ECO:0000269|PubMed:8255296}.
CC -!- ACTIVITY REGULATION: In resting state, adopts an open conformation,
CC anion-binding promoting the inactive configuration. Upon aromatic amino
CC acid-binding, the groove in the extracellular venus flytrap module is
CC closed, thereby inducing the formation of a novel homodimer interface
CC between subunits. Calcium ions stabilize the active state by enhancing
CC homodimer interactions between membrane-proximal domains to fully
CC activate the receptor. {ECO:0000250|UniProtKB:P41180}.
CC -!- SUBUNIT: Homodimer; disulfide-linked. Interacts with VCP and RNF19A (By
CC similarity). Interacts with ARRB1 (By similarity).
CC {ECO:0000250|UniProtKB:P41180, ECO:0000250|UniProtKB:P48442}.
CC -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P41180};
CC Multi-pass membrane protein {ECO:0000250|UniProtKB:P41180}.
CC -!- DOMAIN: The extracellular regions of the homodimer interact in a side-
CC by-side fashion while facing opposite directions. Each extracellular
CC region consists of three domains, LB1 (ligand-binding 1), LB2 and CR
CC (cysteine-rich). The two lobe-shaped domains LB1 and LB2 form a venus
CC flytrap module. In the inactive configuration, the venus flytrap
CC modules of both protomers are in the open conformation associated with
CC the resting state (open-open) and the interdomain cleft is empty. In
CC addition, each protomer contains three anions, which reinforce the
CC inactive conformation, and one calcium ion. In the active
CC configuration, both protomers of extracellular regions have the closed
CC conformation associated with agonist-binding (closed-closed). The
CC ligand-binding cleft of each protomer is solely occupied by an aromatic
CC amino-acid. Calcium is bound at four novel sites, including one at the
CC homodimer interface. Agonist-binding induces large conformational
CC changes within the extracellular region homodimer: first, the venus
CC flytrap module of each protomer undergoes domain closure. Second, the
CC LB2 regions of the two protomers approach each other, resulting in an
CC expansion of the homodimer interactions involving LB2 domains. Third,
CC the CR regions of the two subunits interact to form a large homodimer
CC interface that is unique to the active state. The CR regions are
CC brought into close contact by the motion involving LB2 since the two
CC domains are rigidly associated within each subunit.
CC {ECO:0000250|UniProtKB:P41180}.
CC -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:P41180}.
CC -!- PTM: Ubiquitinated by RNF19A; which induces proteasomal degradation.
CC {ECO:0000250|UniProtKB:P41180}.
CC -!- SIMILARITY: Belongs to the G-protein coupled receptor 3 family.
CC {ECO:0000305}.
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DR EMBL; S67307; AAB29171.1; -; mRNA.
DR PIR; S40476; S40476.
DR RefSeq; NP_776427.1; NM_174002.3.
DR RefSeq; XP_005201442.1; XM_005201385.3.
DR RefSeq; XP_010799466.1; XM_010801164.2.
DR AlphaFoldDB; P35384; -.
DR SMR; P35384; -.
DR BioGRID; 158410; 1.
DR STRING; 9913.ENSBTAP00000005042; -.
DR BindingDB; P35384; -.
DR ChEMBL; CHEMBL1075316; -.
DR DrugCentral; P35384; -.
DR PaxDb; P35384; -.
DR Ensembl; ENSBTAT00000005042; ENSBTAP00000005042; ENSBTAG00000003865.
DR Ensembl; ENSBTAT00000084319; ENSBTAP00000059078; ENSBTAG00000003865.
DR GeneID; 281038; -.
DR KEGG; bta:281038; -.
DR CTD; 846; -.
DR VEuPathDB; HostDB:ENSBTAG00000003865; -.
DR VGNC; VGNC:26788; CASR.
DR eggNOG; KOG1056; Eukaryota.
DR GeneTree; ENSGT00940000157596; -.
DR InParanoid; P35384; -.
DR OMA; CPDDSWS; -.
DR OrthoDB; 327938at2759; -.
DR PRO; PR:P35384; -.
DR Proteomes; UP000009136; Chromosome 1.
DR Bgee; ENSBTAG00000003865; Expressed in adenohypophysis and 20 other tissues.
DR GO; GO:0043679; C:axon terminus; ISS:AgBase.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0016597; F:amino acid binding; ISS:UniProtKB.
DR GO; GO:0005509; F:calcium ion binding; ISS:UniProtKB.
DR GO; GO:0004930; F:G protein-coupled receptor activity; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0070509; P:calcium ion import; IEA:Ensembl.
DR GO; GO:0006816; P:calcium ion transport; ISS:AgBase.
DR GO; GO:0006874; P:cellular calcium ion homeostasis; ISS:UniProtKB.
DR GO; GO:0005513; P:detection of calcium ion; ISS:UniProtKB.
DR GO; GO:0007186; P:G protein-coupled receptor signaling pathway; ISS:UniProtKB.
DR GO; GO:0007254; P:JNK cascade; ISS:AgBase.
DR GO; GO:0001503; P:ossification; ISS:AgBase.
DR GO; GO:0032781; P:positive regulation of ATP-dependent activity; IEA:Ensembl.
DR GO; GO:0008284; P:positive regulation of cell population proliferation; ISS:AgBase.
DR GO; GO:0010628; P:positive regulation of gene expression; IEA:Ensembl.
DR GO; GO:0051924; P:regulation of calcium ion transport; IBA:GO_Central.
DR GO; GO:0042311; P:vasodilation; ISS:AgBase.
DR Gene3D; 2.10.50.30; -; 1.
DR InterPro; IPR001828; ANF_lig-bd_rcpt.
DR InterPro; IPR000337; GPCR_3.
DR InterPro; IPR011500; GPCR_3_9-Cys_dom.
DR InterPro; IPR038550; GPCR_3_9-Cys_sf.
DR InterPro; IPR017978; GPCR_3_C.
DR InterPro; IPR000068; GPCR_3_Ca_sens_rcpt-rel.
DR InterPro; IPR017979; GPCR_3_CS.
DR InterPro; IPR028082; Peripla_BP_I.
DR PANTHER; PTHR24061; PTHR24061; 1.
DR Pfam; PF00003; 7tm_3; 1.
DR Pfam; PF01094; ANF_receptor; 1.
DR Pfam; PF07562; NCD3G; 1.
DR PRINTS; PR00592; CASENSINGR.
DR PRINTS; PR00248; GPCRMGR.
DR SUPFAM; SSF53822; SSF53822; 1.
DR PROSITE; PS00979; G_PROTEIN_RECEP_F3_1; 1.
DR PROSITE; PS00980; G_PROTEIN_RECEP_F3_2; 1.
DR PROSITE; PS00981; G_PROTEIN_RECEP_F3_3; 1.
DR PROSITE; PS50259; G_PROTEIN_RECEP_F3_4; 1.
PE 2: Evidence at transcript level;
KW Calcium; Cell membrane; Disulfide bond; G-protein coupled receptor;
KW Glycoprotein; Membrane; Metal-binding; Phosphoprotein; Receptor;
KW Reference proteome; Signal; Transducer; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT SIGNAL 1..19
FT /evidence="ECO:0000255"
FT CHAIN 20..1085
FT /note="Extracellular calcium-sensing receptor"
FT /id="PRO_0000012945"
FT TOPO_DOM 20..613
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 614..636
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 637..650
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 651..671
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 672..682
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 683..701
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 702..725
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 726..746
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 747..770
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 771..793
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 794..806
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 807..829
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 830..837
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 838..863
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 864..1085
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 23..189
FT /note="Ligand-binding 1 (LB1)"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 190..325
FT /note="Ligand-binding 2 (LB2)"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 543..613
FT /note="Cysteine-rich (CR)"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 881..901
FT /note="Interaction with RNF19A"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 893..969
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1034..1058
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 893..946
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 947..964
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 67..71
FT /ligand="phosphate"
FT /ligand_id="ChEBI:CHEBI:43474"
FT /ligand_note="required for structural stability of the
FT receptor"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 82
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 85
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 88
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 89
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 101
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 146
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 148
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 169
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 171
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 232
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 235
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 298
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 416..418
FT /ligand="phosphate"
FT /ligand_id="ChEBI:CHEBI:43474"
FT /ligand_note="required for structural stability of the
FT receptor"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 558
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT MOD_RES 921
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QY96"
FT MOD_RES 1068
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QY96"
FT CARBOHYD 91
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 131
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 262
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 288
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 401
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 447
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 469
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 489
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 542
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 595
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 61..102
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 130
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 132
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 237..562
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 359..396
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 438..450
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 543..563
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 547..566
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 569..583
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 586..599
FT /evidence="ECO:0000250|UniProtKB:P41180"
SQ SEQUENCE 1085 AA; 121171 MW; 5D66DE8C9CD13E47 CRC64;
MALYSCCWIL LAFSTWCTSA YGPDQRAQKK GDIILGGLFP IHFGVAVKDQ DLKSRPESVE
CIRYNFRGFR WLQAMIFAIE EINSSPALLP NMTLGYRIFD TCNTVSKALE ATLSFVAQNK
IDSLNLDEFC NCSEHIPSTI AVVGATGSGI STAVANLLGL FYIPQVSYAS SSRLLSNKNQ
FKSFLRTIPN DEHQATAMAD IIEYFRWNWV GTIAADDDYG RPGIEKFREE AEERDICIDF
SELISQYSDE EKIQQVVEVI QNSTAKVIVV FSSGPDLEPL IKEIVRRNIT GRIWLASEAW
ASSSLIAMPE YFHVVGGTIG FGLKAGQIPG FREFLQKVHP RKSVHNGFAK EFWEETFNCH
LQEGAKGPLP VDTFLRGHEE GGARLSNSPT AFRPLCTGEE NISSVETPYM DYTHLRISYN
VYLAVYSIAH ALQDIYTCIP GRGLFTNGSC ADIKKVEAWQ VLKHLRHLNF TSNMGEQVTF
DECGDLAGNY SIINWHLSPE DGSIVFKEVG YYNVYAKKGE RLFINDEKIL WSGFSREVPF
SNCSRDCLAG TRKGIIEGEP TCCFECVECP DGEYSDETDA SACDKCPDDF WSNENHTSCI
AKEIEFLSWT EPFGIALTLF AVLGIFLTAF VLGVFIKFRN TPIVKATNRE LSYLLLFSLL
CCFSSSLFFI GEPQDWTCRL RQPAFGISFV LCISCILVKT NRVLLVFEAK IPTSFHRKWW
GLNLQFLLVF LCTFMQIVIC AIWLNTAPPS SYRNHELEDE IIFITCHEGS LMALGFLIGY
TCLLAAICFF FAFKSRKLPE NFNEAKFITF SMLIFFIVWI SFIPAYASTY GKFVSAVEVI
AILAASFGLL ACIFFNKVYI ILFKPSRNTI EEVRCSTAAH AFKVAARATL RRSNVSRQRS
SSLGGSTGST PSSSISSKSN SEDPFPQQQP KRQKQPQPLA LSPHNAQQPQ PRPPSTPQPQ
PQSQQPPRCK QKVIFGSGTV TFSLSFDEPQ KTAVAHRNST HQTSLEAQKN NDALTKHQAL
LPLQCGETDS ELTSQETGLQ GPVGEDHQLE MEDPEEMSPA LVVSNSRSFV ISGGGSTVTE
NMLRS
