O62714 · CASR_PIG

  • Protein
    Extracellular calcium-sensing receptor
  • Gene
    CASR
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at transcript level
  • Annotation score
    5/5

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).

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).

Features

Showing features for binding site.

TypeIDPosition(s)Description
Binding site66-70phosphate (UniProtKB | ChEBI); required for structural stability of the receptor
Binding site81Ca2+ (UniProtKB | ChEBI)
Binding site84Ca2+ (UniProtKB | ChEBI)
Binding site87Ca2+ (UniProtKB | ChEBI)
Binding site88Ca2+ (UniProtKB | ChEBI)
Binding site100Ca2+ (UniProtKB | ChEBI)
Binding site145Ca2+ (UniProtKB | ChEBI)
Binding site147L-tryptophan (UniProtKB | ChEBI)
Binding site168L-tryptophan (UniProtKB | ChEBI)
Binding site170L-tryptophan (UniProtKB | ChEBI)
Binding site231Ca2+ (UniProtKB | ChEBI)
Binding site234Ca2+ (UniProtKB | ChEBI)
Binding site297L-tryptophan (UniProtKB | ChEBI)
Binding site415-417phosphate (UniProtKB | ChEBI); required for structural stability of the receptor
Binding site557Ca2+ (UniProtKB | ChEBI)

GO annotations

AspectTerm
Cellular Componentplasma membrane
Molecular Functionamino acid binding
Molecular Functioncalcium ion binding
Molecular FunctionG protein-coupled receptor activity
Molecular Functionprotein homodimerization activity
Biological Processdetection of calcium ion
Biological ProcessG protein-coupled receptor signaling pathway
Biological Processintracellular calcium ion homeostasis
Biological Processregulation of calcium ion transport

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    Extracellular calcium-sensing receptor
  • Short names
    CaSR
  • Alternative names
    • Parathyroid cell calcium-sensing receptor (PCaR1)

Gene names

    • Name
      CASR
    • Synonyms
      PCAR1

Organism names

  • Taxonomic identifier
  • Strain
    • Belgian Landrace
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Suina > Suidae > Sus

Accessions

  • Primary accession
    O62714
  • Secondary accessions
    • F1SQ21
    • O62715
    • O62716

Proteomes

Subcellular Location

Cell membrane
; Multi-pass membrane protein

Features

Showing features for topological domain, transmembrane.

TypeIDPosition(s)Description
Topological domain20-612Extracellular
Transmembrane613-635Helical; Name=1
Topological domain636-649Cytoplasmic
Transmembrane650-670Helical; Name=2
Topological domain671-681Extracellular
Transmembrane682-700Helical; Name=3
Topological domain701-724Cytoplasmic
Transmembrane725-745Helical; Name=4
Topological domain746-769Extracellular
Transmembrane770-792Helical; Name=5
Topological domain793-805Cytoplasmic
Transmembrane806-828Helical; Name=6
Topological domain829-836Extracellular
Transmembrane837-862Helical; Name=7
Topological domain863-1079Cytoplasmic

Keywords

PTM/Processing

Features

Showing features for signal, chain, disulfide bond, glycosylation, modified residue.

TypeIDPosition(s)Description
Signal1-19
ChainPRO_000020689420-1079Extracellular calcium-sensing receptor
Disulfide bond60↔101
Glycosylation90N-linked (GlcNAc...) asparagine
Disulfide bond129Interchain
Glycosylation130N-linked (GlcNAc...) asparagine
Disulfide bond131Interchain
Disulfide bond236↔561
Glycosylation261N-linked (GlcNAc...) asparagine
Glycosylation287N-linked (GlcNAc...) asparagine
Disulfide bond358↔395
Glycosylation386N-linked (GlcNAc...) asparagine
Glycosylation400N-linked (GlcNAc...) asparagine
Disulfide bond437↔449
Glycosylation446N-linked (GlcNAc...) asparagine
Glycosylation468N-linked (GlcNAc...) asparagine
Glycosylation488N-linked (GlcNAc...) asparagine
Glycosylation541N-linked (GlcNAc...) asparagine
Disulfide bond542↔562
Disulfide bond546↔565
Disulfide bond568↔582
Disulfide bond585↔598
Glycosylation594N-linked (GlcNAc...) asparagine
Modified residue920Phosphoserine
Modified residue1062Phosphoserine

Post-translational modification

N-glycosylated.
Ubiquitinated by RNF19A; which induces proteasomal degradation.

Keywords

Proteomic databases

PTM databases

Interaction

Subunit

Homodimer; disulfide-linked. Interacts with VCP and RNF19A (By similarity).
Interacts with ARRB1 (By similarity).

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for region, compositional bias.

TypeIDPosition(s)Description
Region22-188Ligand-binding 1 (LB1)
Region189-324Ligand-binding 2 (LB2)
Region542-612Cysteine-rich (CR)
Region880-900Interaction with RNF19A
Compositional bias892-923Polar residues
Region892-963Disordered

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

Keywords

Phylogenomic databases

Family and domain databases

Protein family/group databases

Sequence

  • Sequence status
    Complete
  • Sequence processing
    The displayed sequence is further processed into a mature form.
  • Length
    1,079
  • Mass (Da)
    120,361
  • Last updated
    2017-05-10 v3
  • Checksum
    D018DB2983E0FCCA
MAFSSCCWILLALTWCTSAYGPDQRAQKKGDIILGGLFPIHFGVAAKDQNLESRPESVECIRYNFRGFRWLQAMIFAIEEINSSPALLPNMTLGYRIFDTCNTVSKALEATLSFVAQNKIDSLNLDEFCNCSEHIPSTIAVVGATGSGISTAVANLLGLFYIPQVSYASSSRLLSNKNQFKSFLRTIPNDEHQATAMADIIEYFRWNWVGTIAADDDYGRPGIEKFREEAEERDICIDFSELISQYSDEEEIQQVVEVIQNSTAKVIVVFSSGPDLEPLIKEIVRRNITGKIWLASEAWASSSLIAMPEYFHVVGGTIGFALKAGQIPGFREFLQKVHPSKSVHNGFAKEFWEETFNCHLQEGAKGPLTTDTFLRGHEEGGGRISNSSTAFRPLCTGDENISSVETPYMDYTHLRISYNVYLAVYSIAHALQDIYTCIPGRGLFTNGSCADIKKVEAWQVLKHLRHLNFTSNMGEQVTFDEYGDLAGNYSIINWHLSPEDGSIVFKEVGYYNVYAKKGERLFINEEKILWSGFSREVPFSNCSRDCLAGTRKGIIEGEPTCCFECVECPDGEYSDETDASACDKCPDDFWSNENHTSCIAKEIEFLSWTEPFGIALTLFAVLGIFLTAFVLGVFIKFRNTPIVKATNRELSYLLLFSLLCCFSSSLFFIGEPQDWTCRLRQPAFGISFVLCISCILVKTNRVLLVFEAKIPTSFHRKWWGLNLQFLLVFLCTFMQIVICAIWLYTAPPSSYRNHELEDEIIFITCHEGSLMALGFLIGYTCLLAAICFFFAFKSRKLPENFNEAKFITFSMLIFFIVWISFIPAYASTYGKFVSAVEVIAILAASFGLLACIFFNKVYIILFKPSRNTIEEVRCSTAAHAFKVAARATLRRSNVSRQRSSSLGGSTGSTPSSSISSKSNSEDPFPQPERQKKQQPLALTQHVPQPQAPSTPQPQPQLQQQPRCKQKVIFGSGTVTFSLSFDEPQKSATAHRNSTHQNSLEAQKNNDALTRHQALLPLQCGEADAELTAQETGLQGSVGGDHHPEMEDPEEMSPALVMSNSRSFVISGGGSTVTENMLHS

Computationally mapped potential isoform sequences

There are 2 potential isoforms mapped to this entry

View all
EntryEntry nameGene nameLength
L0HSA9L0HSA9_PIGCASR1089
A0A8D1I332A0A8D1I332_PIGCASR1002

Features

Showing features for sequence conflict, compositional bias.

TypeIDPosition(s)Description
Sequence conflict633in Ref. 3; AAC15660/AAC15661/AAC15662
Compositional bias892-923Polar residues
Sequence conflict981in Ref. 3; AAC15660/AAC15661/AAC15662
Sequence conflict986-988in Ref. 3; AAC15660/AAC15661/AAC15662

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
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

Genome annotation databases

Similar Proteins

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