O62714 · CASR_PIG
- ProteinExtracellular calcium-sensing receptor
- GeneCASR
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids1079 (go to sequence)
- Protein existenceEvidence at transcript level
- Annotation score5/5
Function
function
G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis. Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands (By similarity).
The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation (By similarity).
The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system. The G-protein-coupled receptor activity is activated by a co-agonist mechanism: aromatic amino acids, such as Trp or Phe, act concertedly with divalent cations, such as calcium or magnesium, to achieve full receptor activation (By similarity).
Activity regulation
In resting state, adopts an open conformation, anion-binding promoting the inactive configuration (By similarity).
Upon aromatic amino acid-binding, the groove in the extracellular venus flytrap module is closed, thereby inducing the formation of a novel homodimer interface between subunits (By similarity).
Calcium ions stabilize the active state by enhancing homodimer interactions between membrane-proximal domains to fully activate the receptor (By similarity).
In contrast to human protein, not activated by AMG 416, a D-amino acid-containing peptide agonist: this is probably due to the absence of a Cys residue at position 482, which forms a disulfide bond with the AMG 416 peptide agonist in human and that is replaced by a Tyr residue in pig (PubMed:26290606).
Upon aromatic amino acid-binding, the groove in the extracellular venus flytrap module is closed, thereby inducing the formation of a novel homodimer interface between subunits (By similarity).
Calcium ions stabilize the active state by enhancing homodimer interactions between membrane-proximal domains to fully activate the receptor (By similarity).
In contrast to human protein, not activated by AMG 416, a D-amino acid-containing peptide agonist: this is probably due to the absence of a Cys residue at position 482, which forms a disulfide bond with the AMG 416 peptide agonist in human and that is replaced by a Tyr residue in pig (PubMed:26290606).
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 66-70 | phosphate (UniProtKB | ChEBI); required for structural stability of the receptor | ||||
Sequence: RGFRW | ||||||
Binding site | 81 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: I | ||||||
Binding site | 84 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 87 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: L | ||||||
Binding site | 88 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: L | ||||||
Binding site | 100 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 145 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 147 | L-tryptophan (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 168 | L-tryptophan (UniProtKB | ChEBI) | ||||
Sequence: A | ||||||
Binding site | 170 | L-tryptophan (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 231 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 234 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: D | ||||||
Binding site | 297 | L-tryptophan (UniProtKB | ChEBI) | ||||
Sequence: E | ||||||
Binding site | 415-417 | phosphate (UniProtKB | ChEBI); required for structural stability of the receptor | ||||
Sequence: RIS | ||||||
Binding site | 557 | Ca2+ (UniProtKB | ChEBI) | ||||
Sequence: G |
GO annotations
Aspect | Term | |
---|---|---|
Cellular Component | plasma membrane | |
Molecular Function | amino acid binding | |
Molecular Function | calcium ion binding | |
Molecular Function | G protein-coupled receptor activity | |
Molecular Function | protein homodimerization activity | |
Biological Process | detection of calcium ion | |
Biological Process | G protein-coupled receptor signaling pathway | |
Biological Process | intracellular calcium ion homeostasis | |
Biological Process | regulation of calcium ion transport |
Keywords
- Molecular function
- Ligand
Enzyme and pathway databases
Names & Taxonomy
Protein names
- Recommended nameExtracellular calcium-sensing receptor
- Short namesCaSR
- Alternative names
Gene names
Organism names
- Organism
- Strain
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Suina > Suidae > Sus
Accessions
- Primary accessionO62714
- Secondary accessions
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Cell membrane ; Multi-pass membrane protein
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 20-612 | Extracellular | ||||
Sequence: YGPDQRAQKKGDIILGGLFPIHFGVAAKDQNLESRPESVECIRYNFRGFRWLQAMIFAIEEINSSPALLPNMTLGYRIFDTCNTVSKALEATLSFVAQNKIDSLNLDEFCNCSEHIPSTIAVVGATGSGISTAVANLLGLFYIPQVSYASSSRLLSNKNQFKSFLRTIPNDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFSELISQYSDEEEIQQVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWASSSLIAMPEYFHVVGGTIGFALKAGQIPGFREFLQKVHPSKSVHNGFAKEFWEETFNCHLQEGAKGPLTTDTFLRGHEEGGGRISNSSTAFRPLCTGDENISSVETPYMDYTHLRISYNVYLAVYSIAHALQDIYTCIPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTSNMGEQVTFDEYGDLAGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINEEKILWSGFSREVPFSNCSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACDKCPDDFWSNENHTSCIAKEIEFLSWTEPF | ||||||
Transmembrane | 613-635 | Helical; Name=1 | ||||
Sequence: GIALTLFAVLGIFLTAFVLGVFI | ||||||
Topological domain | 636-649 | Cytoplasmic | ||||
Sequence: KFRNTPIVKATNRE | ||||||
Transmembrane | 650-670 | Helical; Name=2 | ||||
Sequence: LSYLLLFSLLCCFSSSLFFIG | ||||||
Topological domain | 671-681 | Extracellular | ||||
Sequence: EPQDWTCRLRQ | ||||||
Transmembrane | 682-700 | Helical; Name=3 | ||||
Sequence: PAFGISFVLCISCILVKTN | ||||||
Topological domain | 701-724 | Cytoplasmic | ||||
Sequence: RVLLVFEAKIPTSFHRKWWGLNLQ | ||||||
Transmembrane | 725-745 | Helical; Name=4 | ||||
Sequence: FLLVFLCTFMQIVICAIWLYT | ||||||
Topological domain | 746-769 | Extracellular | ||||
Sequence: APPSSYRNHELEDEIIFITCHEGS | ||||||
Transmembrane | 770-792 | Helical; Name=5 | ||||
Sequence: LMALGFLIGYTCLLAAICFFFAF | ||||||
Topological domain | 793-805 | Cytoplasmic | ||||
Sequence: KSRKLPENFNEAK | ||||||
Transmembrane | 806-828 | Helical; Name=6 | ||||
Sequence: FITFSMLIFFIVWISFIPAYAST | ||||||
Topological domain | 829-836 | Extracellular | ||||
Sequence: YGKFVSAV | ||||||
Transmembrane | 837-862 | Helical; Name=7 | ||||
Sequence: EVIAILAASFGLLACIFFNKVYIILF | ||||||
Topological domain | 863-1079 | Cytoplasmic | ||||
Sequence: KPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRQRSSSLGGSTGSTPSSSISSKSNSEDPFPQPERQKKQQPLALTQHVPQPQAPSTPQPQPQLQQQPRCKQKVIFGSGTVTFSLSFDEPQKSATAHRNSTHQNSLEAQKNNDALTRHQALLPLQCGEADAELTAQETGLQGSVGGDHHPEMEDPEEMSPALVMSNSRSFVISGGGSTVTENMLHS |
Keywords
- Cellular component
PTM/Processing
Features
Showing features for signal, chain, disulfide bond, glycosylation, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Signal | 1-19 | |||||
Sequence: MAFSSCCWILLALTWCTSA | ||||||
Chain | PRO_0000206894 | 20-1079 | Extracellular calcium-sensing receptor | |||
Sequence: YGPDQRAQKKGDIILGGLFPIHFGVAAKDQNLESRPESVECIRYNFRGFRWLQAMIFAIEEINSSPALLPNMTLGYRIFDTCNTVSKALEATLSFVAQNKIDSLNLDEFCNCSEHIPSTIAVVGATGSGISTAVANLLGLFYIPQVSYASSSRLLSNKNQFKSFLRTIPNDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFSELISQYSDEEEIQQVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWASSSLIAMPEYFHVVGGTIGFALKAGQIPGFREFLQKVHPSKSVHNGFAKEFWEETFNCHLQEGAKGPLTTDTFLRGHEEGGGRISNSSTAFRPLCTGDENISSVETPYMDYTHLRISYNVYLAVYSIAHALQDIYTCIPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTSNMGEQVTFDEYGDLAGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINEEKILWSGFSREVPFSNCSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACDKCPDDFWSNENHTSCIAKEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIKFRNTPIVKATNRELSYLLLFSLLCCFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRVLLVFEAKIPTSFHRKWWGLNLQFLLVFLCTFMQIVICAIWLYTAPPSSYRNHELEDEIIFITCHEGSLMALGFLIGYTCLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFVSAVEVIAILAASFGLLACIFFNKVYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRQRSSSLGGSTGSTPSSSISSKSNSEDPFPQPERQKKQQPLALTQHVPQPQAPSTPQPQPQLQQQPRCKQKVIFGSGTVTFSLSFDEPQKSATAHRNSTHQNSLEAQKNNDALTRHQALLPLQCGEADAELTAQETGLQGSVGGDHHPEMEDPEEMSPALVMSNSRSFVISGGGSTVTENMLHS | ||||||
Disulfide bond | 60↔101 | |||||
Sequence: CIRYNFRGFRWLQAMIFAIEEINSSPALLPNMTLGYRIFDTC | ||||||
Glycosylation | 90 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 129 | Interchain | ||||
Sequence: C | ||||||
Glycosylation | 130 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 131 | Interchain | ||||
Sequence: C | ||||||
Disulfide bond | 236↔561 | |||||
Sequence: CIDFSELISQYSDEEEIQQVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWASSSLIAMPEYFHVVGGTIGFALKAGQIPGFREFLQKVHPSKSVHNGFAKEFWEETFNCHLQEGAKGPLTTDTFLRGHEEGGGRISNSSTAFRPLCTGDENISSVETPYMDYTHLRISYNVYLAVYSIAHALQDIYTCIPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTSNMGEQVTFDEYGDLAGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINEEKILWSGFSREVPFSNCSRDCLAGTRKGIIEGEPTC | ||||||
Glycosylation | 261 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 287 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 358↔395 | |||||
Sequence: CHLQEGAKGPLTTDTFLRGHEEGGGRISNSSTAFRPLC | ||||||
Glycosylation | 386 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 400 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 437↔449 | |||||
Sequence: CIPGRGLFTNGSC | ||||||
Glycosylation | 446 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 468 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 488 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Glycosylation | 541 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Disulfide bond | 542↔562 | |||||
Sequence: CSRDCLAGTRKGIIEGEPTCC | ||||||
Disulfide bond | 546↔565 | |||||
Sequence: CLAGTRKGIIEGEPTCCFEC | ||||||
Disulfide bond | 568↔582 | |||||
Sequence: CPDGEYSDETDASAC | ||||||
Disulfide bond | 585↔598 | |||||
Sequence: CPDDFWSNENHTSC | ||||||
Glycosylation | 594 | N-linked (GlcNAc...) asparagine | ||||
Sequence: N | ||||||
Modified residue | 920 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 1062 | Phosphoserine | ||||
Sequence: S |
Post-translational modification
N-glycosylated.
Ubiquitinated by RNF19A; which induces proteasomal degradation.
Keywords
- PTM
Proteomic databases
PTM databases
Interaction
Subunit
Homodimer; disulfide-linked. Interacts with VCP and RNF19A (By similarity).
Interacts with ARRB1 (By similarity).
Interacts with ARRB1 (By similarity).
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 22-188 | Ligand-binding 1 (LB1) | ||||
Sequence: PDQRAQKKGDIILGGLFPIHFGVAAKDQNLESRPESVECIRYNFRGFRWLQAMIFAIEEINSSPALLPNMTLGYRIFDTCNTVSKALEATLSFVAQNKIDSLNLDEFCNCSEHIPSTIAVVGATGSGISTAVANLLGLFYIPQVSYASSSRLLSNKNQFKSFLRTIP | ||||||
Region | 189-324 | Ligand-binding 2 (LB2) | ||||
Sequence: NDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFSELISQYSDEEEIQQVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWASSSLIAMPEYFHVVGGTIGFALKA | ||||||
Region | 542-612 | Cysteine-rich (CR) | ||||
Sequence: CSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACDKCPDDFWSNENHTSCIAKEIEFLSWTEPF | ||||||
Region | 880-900 | Interaction with RNF19A | ||||
Sequence: AFKVAARATLRRSNVSRQRSS | ||||||
Compositional bias | 892-923 | Polar residues | ||||
Sequence: SNVSRQRSSSLGGSTGSTPSSSISSKSNSEDP | ||||||
Region | 892-963 | Disordered | ||||
Sequence: SNVSRQRSSSLGGSTGSTPSSSISSKSNSEDPFPQPERQKKQQPLALTQHVPQPQAPSTPQPQPQLQQQPRC |
Domain
The extracellular regions of the homodimer interact in a side-by-side fashion while facing opposite directions. Each extracellular region consists of three domains, LB1 (ligand-binding 1), LB2 and CR (cysteine-rich). The two lobe-shaped domains LB1 and LB2 form a venus flytrap module. In the inactive configuration, the venus flytrap modules of both protomers are in the open conformation associated with the resting state (open-open) and the interdomain cleft is empty. In addition, each protomer contains three anions, which reinforce the inactive conformation, and one calcium ion. In the active configuration, both protomers of extracellular regions have the closed conformation associated with agonist-binding (closed-closed). The ligand-binding cleft of each protomer is solely occupied by an aromatic amino-acid. Calcium is bound at four novel sites, including one at the homodimer interface. Agonist-binding induces large conformational changes within the extracellular region homodimer: first, the venus flytrap module of each protomer undergoes domain closure. Second, the LB2 regions of the two protomers approach each other, resulting in an expansion of the homodimer interactions involving LB2 domains. Third, the CR regions of the two subunits interact to form a large homodimer interface that is unique to the active state. The CR regions are brought into close contact by the motion involving LB2 since the two domains are rigidly associated within each subunit.
Sequence similarities
Belongs to the G-protein coupled receptor 3 family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Protein family/group databases
Sequence
- Sequence statusComplete
- Sequence processingThe displayed sequence is further processed into a mature form.
- Length1,079
- Mass (Da)120,361
- Last updated2017-05-10 v3
- ChecksumD018DB2983E0FCCA
Computationally mapped potential isoform sequences
There are 2 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
L0HSA9 | L0HSA9_PIG | CASR | 1089 | ||
A0A8D1I332 | A0A8D1I332_PIG | CASR | 1002 |
Features
Showing features for sequence conflict, compositional bias.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Sequence conflict | 633 | in Ref. 3; AAC15660/AAC15661/AAC15662 | ||||
Sequence: V → A | ||||||
Compositional bias | 892-923 | Polar residues | ||||
Sequence: SNVSRQRSSSLGGSTGSTPSSSISSKSNSEDP | ||||||
Sequence conflict | 981 | in Ref. 3; AAC15660/AAC15661/AAC15662 | ||||
Sequence: D → H | ||||||
Sequence conflict | 986-988 | in Ref. 3; AAC15660/AAC15661/AAC15662 | ||||
Sequence: SAT → NAM |
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
KT309043 EMBL· GenBank· DDBJ | ALB08481.1 EMBL· GenBank· DDBJ | mRNA | ||
CU694886 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
AF041025 EMBL· GenBank· DDBJ | AAC15660.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF041026 EMBL· GenBank· DDBJ | AAC15661.1 EMBL· GenBank· DDBJ | Genomic DNA | ||
AF041027 EMBL· GenBank· DDBJ | AAC15662.1 EMBL· GenBank· DDBJ | Genomic DNA |