CASR_PIG
ID CASR_PIG Reviewed; 1079 AA.
AC O62714; F1SQ21; O62715; O62716;
DT 11-OCT-2004, integrated into UniProtKB/Swiss-Prot.
DT 10-MAY-2017, sequence version 3.
DT 03-AUG-2022, entry version 102.
DE RecName: Full=Extracellular calcium-sensing receptor;
DE Short=CaSR;
DE AltName: Full=Parathyroid cell calcium-sensing receptor;
DE Short=PCaR1;
DE Flags: Precursor;
GN Name=CASR; Synonyms=PCAR1;
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND ACTIVITY REGULATION.
RC TISSUE=Kidney;
RX PubMed=26290606; DOI=10.1124/mol.115.098392;
RA Alexander S.T., Hunter T., Walter S., Dong J., Maclean D., Baruch A.,
RA Subramanian R., Tomlinson J.;
RT "Critical cysteine residues in both the calcium-sensing receptor and the
RT allosteric activator AMG 416 underlie the mechanism of action.";
RL Mol. Pharmacol. 88:853-865(2015).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RG Porcine genome sequencing project;
RL Submitted (NOV-2009) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 585-702; 850-908 AND 958-988.
RC STRAIN=Belgian Landrace;
RX PubMed=10449918; DOI=10.1159/000015313;
RA Van Poucke M., Toernsten A., Mattheeuws M., Van Zeveren A., Peelman L.J.,
RA Chowdhary B.P.;
RT "Comparative mapping between human chromosome 3 and porcine chromosome
RT 13.";
RL Cytogenet. Cell Genet. 85:279-284(1999).
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. Senses fluctuations in the circulating
CC calcium concentration and modulates the production of parathyroid
CC hormone (PTH) in parathyroid glands (By similarity). The activity of
CC this receptor is mediated by a G-protein that activates a
CC phosphatidylinositol-calcium second messenger system. The G-protein-
CC coupled receptor activity is activated by a co-agonist mechanism:
CC aromatic amino acids, such as Trp or Phe, act concertedly with divalent
CC cations, such as calcium or magnesium, to achieve full receptor
CC activation (By similarity). {ECO:0000250|UniProtKB:P41180,
CC ECO:0000250|UniProtKB:Q9QY96}.
CC -!- ACTIVITY REGULATION: In resting state, adopts an open conformation,
CC anion-binding promoting the inactive configuration (By similarity).
CC Upon aromatic amino acid-binding, the groove in the extracellular venus
CC flytrap module is closed, thereby inducing the formation of a novel
CC homodimer interface between subunits (By similarity). Calcium ions
CC stabilize the active state by enhancing homodimer interactions between
CC membrane-proximal domains to fully activate the receptor (By
CC similarity). In contrast to human protein, not activated by AMG 416, a
CC D-amino acid-containing peptide agonist: this is probably due to the
CC absence of a Cys residue at position 482, which forms a disulfide bond
CC with the AMG 416 peptide agonist in human and that is replaced by a Tyr
CC residue in pig (PubMed:26290606). {ECO:0000250|UniProtKB:P41180,
CC ECO:0000269|PubMed:26290606}.
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; KT309043; ALB08481.1; -; mRNA.
DR EMBL; CU694886; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AF041025; AAC15660.1; -; Genomic_DNA.
DR EMBL; AF041026; AAC15661.1; -; Genomic_DNA.
DR EMBL; AF041027; AAC15662.1; -; Genomic_DNA.
DR RefSeq; XP_005654095.1; XM_005654038.2.
DR AlphaFoldDB; O62714; -.
DR SMR; O62714; -.
DR STRING; 9823.ENSSSCP00000012651; -.
DR PRIDE; O62714; -.
DR Ensembl; ENSSSCT00005045216; ENSSSCP00005027697; ENSSSCG00005028503.
DR Ensembl; ENSSSCT00005045296; ENSSSCP00005027759; ENSSSCG00005028503.
DR GeneID; 100520980; -.
DR CTD; 846; -.
DR eggNOG; KOG1056; Eukaryota.
DR InParanoid; O62714; -.
DR OMA; CPDDSWS; -.
DR TreeFam; TF331269; -.
DR Reactome; R-SSC-416476; G alpha (q) signalling events.
DR Reactome; R-SSC-418594; G alpha (i) signalling events.
DR Reactome; R-SSC-420499; Class C/3 (Metabotropic glutamate/pheromone receptors).
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
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: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:0051924; P:regulation of calcium ion transport; IBA:GO_Central.
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..1079
FT /note="Extracellular calcium-sensing receptor"
FT /id="PRO_0000206894"
FT TOPO_DOM 20..612
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 613..635
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 636..649
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 650..670
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 671..681
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 682..700
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 701..724
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 725..745
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 746..769
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 770..792
FT /note="Helical; Name=5"
FT /evidence="ECO:0000255"
FT TOPO_DOM 793..805
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 806..828
FT /note="Helical; Name=6"
FT /evidence="ECO:0000255"
FT TOPO_DOM 829..836
FT /note="Extracellular"
FT /evidence="ECO:0000305"
FT TRANSMEM 837..862
FT /note="Helical; Name=7"
FT /evidence="ECO:0000255"
FT TOPO_DOM 863..1079
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT REGION 22..188
FT /note="Ligand-binding 1 (LB1)"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 189..324
FT /note="Ligand-binding 2 (LB2)"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 542..612
FT /note="Cysteine-rich (CR)"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 880..900
FT /note="Interaction with RNF19A"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT REGION 892..963
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 892..923
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 66..70
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 81
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 84
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 87
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 100
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 145
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 147
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 168
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 170
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 231
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 234
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 297
FT /ligand="L-tryptophan"
FT /ligand_id="ChEBI:CHEBI:57912"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT BINDING 415..417
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 557
FT /ligand="Ca(2+)"
FT /ligand_id="ChEBI:CHEBI:29108"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT MOD_RES 920
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QY96"
FT MOD_RES 1062
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9QY96"
FT CARBOHYD 90
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 130
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 261
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 287
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00498"
FT CARBOHYD 386
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 400
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00498"
FT CARBOHYD 446
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 468
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00498"
FT CARBOHYD 488
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00498"
FT CARBOHYD 541
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 594
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT DISULFID 60..101
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 129
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 131
FT /note="Interchain"
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 236..561
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 358..395
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 437..449
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 542..562
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 546..565
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 568..582
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT DISULFID 585..598
FT /evidence="ECO:0000250|UniProtKB:P41180"
FT CONFLICT 633
FT /note="V -> A (in Ref. 3; AAC15660/AAC15661/AAC15662)"
FT /evidence="ECO:0000305"
FT CONFLICT 981
FT /note="D -> H (in Ref. 3; AAC15660/AAC15661/AAC15662)"
FT /evidence="ECO:0000305"
FT CONFLICT 986..988
FT /note="SAT -> NAM (in Ref. 3; AAC15660/AAC15661/AAC15662)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 1079 AA; 120361 MW; D018DB2983E0FCCA CRC64;
MAFSSCCWIL LALTWCTSAY GPDQRAQKKG DIILGGLFPI HFGVAAKDQN LESRPESVEC
IRYNFRGFRW LQAMIFAIEE INSSPALLPN MTLGYRIFDT CNTVSKALEA TLSFVAQNKI
DSLNLDEFCN CSEHIPSTIA VVGATGSGIS TAVANLLGLF YIPQVSYASS SRLLSNKNQF
KSFLRTIPND EHQATAMADI IEYFRWNWVG TIAADDDYGR PGIEKFREEA EERDICIDFS
ELISQYSDEE EIQQVVEVIQ NSTAKVIVVF SSGPDLEPLI KEIVRRNITG KIWLASEAWA
SSSLIAMPEY FHVVGGTIGF ALKAGQIPGF REFLQKVHPS KSVHNGFAKE FWEETFNCHL
QEGAKGPLTT DTFLRGHEEG GGRISNSSTA FRPLCTGDEN ISSVETPYMD YTHLRISYNV
YLAVYSIAHA LQDIYTCIPG RGLFTNGSCA DIKKVEAWQV LKHLRHLNFT SNMGEQVTFD
EYGDLAGNYS IINWHLSPED GSIVFKEVGY YNVYAKKGER LFINEEKILW SGFSREVPFS
NCSRDCLAGT RKGIIEGEPT CCFECVECPD GEYSDETDAS ACDKCPDDFW SNENHTSCIA
KEIEFLSWTE PFGIALTLFA VLGIFLTAFV LGVFIKFRNT PIVKATNREL SYLLLFSLLC
CFSSSLFFIG EPQDWTCRLR QPAFGISFVL CISCILVKTN RVLLVFEAKI PTSFHRKWWG
LNLQFLLVFL CTFMQIVICA IWLYTAPPSS YRNHELEDEI IFITCHEGSL MALGFLIGYT
CLLAAICFFF AFKSRKLPEN FNEAKFITFS MLIFFIVWIS FIPAYASTYG KFVSAVEVIA
ILAASFGLLA CIFFNKVYII LFKPSRNTIE EVRCSTAAHA FKVAARATLR RSNVSRQRSS
SLGGSTGSTP SSSISSKSNS EDPFPQPERQ KKQQPLALTQ HVPQPQAPST PQPQPQLQQQ
PRCKQKVIFG SGTVTFSLSF DEPQKSATAH RNSTHQNSLE AQKNNDALTR HQALLPLQCG
EADAELTAQE TGLQGSVGGD HHPEMEDPEE MSPALVMSNS RSFVISGGGS TVTENMLHS
