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Protein

Extracellular calcium-sensing receptor

Gene

Casr

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

G-protein-coupled receptor that senses changes in the extracellular concentration of calcium ions and plays a key role in maintaining calcium homeostasis (By similarity). Senses fluctuations in the circulating calcium concentration and modulates the production of parathyroid hormone (PTH) in parathyroid glands (PubMed:7493018). The activity of this receptor is mediated by a G-protein that activates a phosphatidylinositol-calcium second messenger system (By similarity). 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).By similarity1 Publication

Enzyme regulationi

In resting state, adopts an open conformation, anion-binding promoting the inactive configuration. 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. Calcium ions stabilize the active state by enhancing homodimer interactions between membrane-proximal domains to fully activate the receptor.By similarity

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi81Calcium; via carbonyl oxygenBy similarity1
Metal bindingi84CalciumBy similarity1
Metal bindingi87Calcium; via carbonyl oxygenBy similarity1
Metal bindingi88Calcium; via carbonyl oxygenBy similarity1
Metal bindingi100CalciumBy similarity1
Metal bindingi145CalciumBy similarity1
Binding sitei147Aromatic amino acidBy similarity1
Binding sitei168Aromatic amino acid; via carbonyl oxygenBy similarity1
Binding sitei170Aromatic amino acidBy similarity1
Metal bindingi231CalciumBy similarity1
Metal bindingi234CalciumBy similarity1
Binding sitei297Aromatic amino acidBy similarity1
Metal bindingi557Calcium; via carbonyl oxygenBy similarity1

GO - Molecular functioni

GO - Biological processi

Keywordsi

Molecular functionG-protein coupled receptor, Receptor, Transducer
LigandCalcium, Metal-binding

Enzyme and pathway databases

ReactomeiR-MMU-416476. G alpha (q) signalling events.
R-MMU-418594. G alpha (i) signalling events.
R-MMU-420499. Class C/3 (Metabotropic glutamate/pheromone receptors).

Names & Taxonomyi

Protein namesi
Recommended name:
Extracellular calcium-sensing receptor
Short name:
CaSR
Alternative name(s):
Parathyroid cell calcium-sensing receptor
Short name:
PCaR1
Gene namesi
Name:CasrImported
Synonyms:Gprc2a
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaMyomorphaMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 16

Organism-specific databases

MGIiMGI:1351351. Casr.

Subcellular locationi

  • Cell membrane By similarity; Multi-pass membrane protein By similarity

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini20 – 612ExtracellularSequence analysisAdd BLAST593
Transmembranei613 – 635Helical; Name=1Sequence analysisAdd BLAST23
Topological domaini636 – 649CytoplasmicSequence analysisAdd BLAST14
Transmembranei650 – 670Helical; Name=2Sequence analysisAdd BLAST21
Topological domaini671 – 681ExtracellularSequence analysisAdd BLAST11
Transmembranei682 – 700Helical; Name=3Sequence analysisAdd BLAST19
Topological domaini701 – 724CytoplasmicSequence analysisAdd BLAST24
Transmembranei725 – 745Helical; Name=4Sequence analysisAdd BLAST21
Topological domaini746 – 769ExtracellularSequence analysisAdd BLAST24
Transmembranei770 – 792Helical; Name=5Sequence analysisAdd BLAST23
Topological domaini793 – 805CytoplasmicSequence analysisAdd BLAST13
Transmembranei806 – 828Helical; Name=6Sequence analysisAdd BLAST23
Topological domaini829 – 836ExtracellularSequence analysis8
Transmembranei837 – 862Helical; Name=7Sequence analysisAdd BLAST26
Topological domaini863 – 1079CytoplasmicSequence analysisAdd BLAST217

GO - Cellular componenti

Keywords - Cellular componenti

Cell membrane, Membrane

Pathology & Biotechi

Disruption phenotypei

Heterozygous mice show benign and modest elevations of serum calcium, magnesium and parathyroid hormone levels as well as hypocalciuria. Homozygous mice show neonatal severe hyperparathyroidism, had markedly elevated serum calcium and parathyroid hormone levels, parathyroid hyperplasia, bone abnormalities, retarded growth and premature death.1 Publication

Chemistry databases

GuidetoPHARMACOLOGYi54.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Signal peptidei1 – 19Sequence analysisAdd BLAST19
ChainiPRO_000001294720 – 1079Extracellular calcium-sensing receptorAdd BLAST1060

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Disulfide bondi60 ↔ 101By similarity
Glycosylationi90N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi129InterchainBy similarity
Glycosylationi130N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi131InterchainBy similarity
Disulfide bondi236 ↔ 561By similarity
Glycosylationi261N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi287N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi358 ↔ 395By similarity
Glycosylationi386N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi437 ↔ 449By similarity
Glycosylationi446N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi468N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi488N-linked (GlcNAc...) asparagineSequence analysis1
Glycosylationi541N-linked (GlcNAc...) asparagineSequence analysis1
Disulfide bondi542 ↔ 562By similarity
Disulfide bondi546 ↔ 565By similarity
Disulfide bondi568 ↔ 582By similarity
Disulfide bondi585 ↔ 598By similarity
Glycosylationi594N-linked (GlcNAc...) asparagineSequence analysis1
Modified residuei920PhosphoserineCombined sources1
Modified residuei1062PhosphoserineCombined sources1

Post-translational modificationi

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

Keywords - PTMi

Disulfide bond, Glycoprotein, Phosphoprotein, Ubl conjugation

Proteomic databases

PaxDbiQ9QY96.
PRIDEiQ9QY96.

PTM databases

iPTMnetiQ9QY96.
PhosphoSitePlusiQ9QY96.

Expressioni

Tissue specificityi

Epidermis, kidney and cartilage.4 Publications

Gene expression databases

BgeeiENSMUSG00000051980.
CleanExiMM_CASR.
GenevisibleiQ9QY96. MM.

Interactioni

Subunit structurei

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

GO - Molecular functioni

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000069080.

Structurei

3D structure databases

ProteinModelPortaliQ9QY96.
SMRiQ9QY96.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni22 – 188Ligand-binding 1 (LB1)By similarityAdd BLAST167
Regioni66 – 70Anion bindingBy similarity5
Regioni189 – 324Ligand-binding 2 (LB2)By similarityAdd BLAST136
Regioni415 – 417Anion bindingBy similarity3
Regioni542 – 612Cysteine-rich (CR)By similarityAdd BLAST71
Regioni880 – 900Interaction with RNF19ABy similarityAdd BLAST21

Domaini

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.By similarity

Sequence similaritiesi

Keywords - Domaini

Signal, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG1056. Eukaryota.
ENOG410XR6W. LUCA.
GeneTreeiENSGT00760000118974.
HOVERGENiHBG052876.
InParanoidiQ9QY96.
KOiK04612.
OMAiMGEQVTF.
OrthoDBiEOG091G01NA.
TreeFamiTF331269.

Family and domain databases

InterProiView protein in InterPro
IPR001828. ANF_lig-bd_rcpt.
IPR000337. GPCR_3.
IPR011500. GPCR_3_9-Cys_dom.
IPR017978. GPCR_3_C.
IPR017979. GPCR_3_CS.
IPR028082. Peripla_BP_I.
PfamiView protein in Pfam
PF00003. 7tm_3. 1 hit.
PF01094. ANF_receptor. 1 hit.
PF07562. NCD3G. 1 hit.
PRINTSiPR00248. GPCRMGR.
SUPFAMiSSF53822. SSF53822. 1 hit.
PROSITEiView protein in PROSITE
PS00979. G_PROTEIN_RECEP_F3_1. 1 hit.
PS00980. G_PROTEIN_RECEP_F3_2. 1 hit.
PS00981. G_PROTEIN_RECEP_F3_3. 1 hit.
PS50259. G_PROTEIN_RECEP_F3_4. 1 hit.

Sequences (2)i

Sequence statusi: Complete.

Sequence processingi: The displayed sequence is further processed into a mature form.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

Isoform A (identifier: Q9QY96-1) [UniParc]FASTAAdd to basket

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MAWFGYCLAL LALTWHSSAY GPDQRAQKKG DIILGGLFPI HFGVAAKDQD
60 70 80 90 100
LKSRPESVEC IRYNFRGFRW LQAMIFAIEE INSSPALLPN MTLGYRIFDT
110 120 130 140 150
CNTVSKALEA TLSFVAQNKI DSLNLDEFCN CSEHIPSTIA VVGATGSGVS
160 170 180 190 200
TAVANLLGLF YIPQVSYASS SRLLSNKNQF KSFLRTIPND EHQATAMADI
210 220 230 240 250
IEYFRWNWVG TIAADDDYGR PGIEKFREEA EERDICIDFS ELISQYSDEE
260 270 280 290 300
EIQQVVEVIQ NSTAKVIVVF SSGPDLEPLI KEIVRRNITG RIWLASEAWA
310 320 330 340 350
SSSLIAMPEY FHVVGGTIGF GLKAGQIPGF REFLQKVHPR KSVHNGFAKE
360 370 380 390 400
FWEETFNCHL QDGAKGPLPV DTFVRSHEEG GNRLLNSSTA FRPLCTGDEN
410 420 430 440 450
INSVETPYMD YEHLRISYNV YLAVYSIAHA LQDIYTCLPG RGLFTNGSCA
460 470 480 490 500
DIKKVEAWQV LKHLRHLNFT NNMGEQVTFD ECGDLVGNYS IINWHLSPED
510 520 530 540 550
GSIVFKEVGY YNVYAKKGER LFINEGKILW SGFSREVPFS NCSRDCQAGT
560 570 580 590 600
RKGIIEGEPT CCFECVECPD GEYSGETDAS ACDKCPDDFW SNENHTSCIA
610 620 630 640 650
KEIEFLAWTE PFGIALTLFA VLGIFLTAFV LGVFIKFRNT PIVKATNREL
660 670 680 690 700
SYLLLFSLLC CFSSSLFFIG EPQDWTCRLR QPAFGISFVL CISCILVKTN
710 720 730 740 750
RVLLVFEAKI PTSFHRKWWG LNLQFLLVFL CTFMQIVICI IWLYTAPPSS
760 770 780 790 800
YRNHELEDEI IFITCHEGSL MALGSLIGYT CLLAAICFFF AFKSRKLPEN
810 820 830 840 850
FNEAKFITFS MLIFFIVWIS FIPAYASTYG KFVSAVEVIA ILAASFGLLA
860 870 880 890 900
CIFFNKVYII LFKPSRNTIE EVRSSTAAHA FKVAARATLR RPNISRKRSS
910 920 930 940 950
SLGGSTGSIP SSSISSKSNS EDRFPQPERQ KQQQPLALTQ QEQQQQPLTL
960 970 980 990 1000
QPQQQQQPQQ PRCKQKVIFG SGTVTFSLSF DEPQKNAMAH RNSMRQNSLE
1010 1020 1030 1040 1050
AQKSNDTLNR HQALLPLQCA EADSEMTIQE TGLQGPMVGD HQPEIESPDE
1060 1070
MSPALVMSTS RSFVISGGGS SVTENILHS
Length:1,079
Mass (Da):120,903
Last modified:October 3, 2012 - v2
Checksum:i8AEF586CDCD93CB3
GO
Isoform B (identifier: Q9QY96-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     461-537: Missing.

Show »
Length:1,002
Mass (Da):111,996
Checksum:i94BF8B687C0FD877
GO

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti45A → S in AAD40638 (PubMed:10652312).Curated1
Sequence conflicti304L → P in AAF00193 (PubMed:10579354).Curated1
Sequence conflicti410D → G in AAD28371 (PubMed:10625662).Curated1
Sequence conflicti410D → G in AAD28372 (PubMed:10625662).Curated1
Sequence conflicti566V → A in AAD40638 (PubMed:10652312).Curated1
Sequence conflicti595H → Y in AAD28371 (PubMed:10625662).Curated1
Sequence conflicti595H → Y in AAD28372 (PubMed:10625662).Curated1
Sequence conflicti610E → V in BAA77688 (Ref. 7) Curated1
Sequence conflicti814F → L in BAA77688 (Ref. 7) Curated1
Sequence conflicti889L → I in AAD40638 (PubMed:10652312).Curated1
Sequence conflicti906 – 908TGS → SGW in AAD40638 (PubMed:10652312).Curated3
Sequence conflicti909I → N in AAD28371 (PubMed:10625662).Curated1
Sequence conflicti909I → N in AAD28372 (PubMed:10625662).Curated1
Sequence conflicti1057M → V in AAD28371 (PubMed:10625662).Curated1
Sequence conflicti1057M → V in AAD28372 (PubMed:10625662).Curated1
Sequence conflicti1064V → A in AAD40638 (PubMed:10652312).Curated1
Sequence conflicti1076I → V in AAD40638 (PubMed:10652312).Curated1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_002036461 – 537Missing in isoform B. CuratedAdd BLAST77

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF110178 mRNA. Translation: AAD28371.1.
AF110179 mRNA. Translation: AAD28372.1.
AF128842 mRNA. Translation: AAD40638.1.
AC074229 Genomic DNA. No translation available.
CH466521 Genomic DNA. Translation: EDK97924.1.
AF068900 mRNA. Translation: AAC19388.1.
AB027140 mRNA. Translation: BAA77688.1.
AF002015 Genomic DNA. Translation: AAC53252.1.
AF159565 mRNA. Translation: AAF00193.1.
CCDSiCCDS28154.1. [Q9QY96-1]
RefSeqiNP_038831.2. NM_013803.3. [Q9QY96-1]
XP_006521792.1. XM_006521729.2. [Q9QY96-1]
XP_006521793.1. XM_006521730.2. [Q9QY96-1]
XP_006521794.1. XM_006521731.3. [Q9QY96-1]
XP_006521795.1. XM_006521732.2. [Q9QY96-1]
UniGeneiMm.103619.
Mm.393142.

Genome annotation databases

EnsembliENSMUST00000063597; ENSMUSP00000069080; ENSMUSG00000051980. [Q9QY96-1]
ENSMUST00000114847; ENSMUSP00000110496; ENSMUSG00000051980. [Q9QY96-2]
ENSMUST00000172826; ENSMUSP00000133500; ENSMUSG00000051980. [Q9QY96-1]
GeneIDi12374.
KEGGimmu:12374.
UCSCiuc007zcp.1. mouse. [Q9QY96-1]
uc012afg.1. mouse. [Q9QY96-2]

Keywords - Coding sequence diversityi

Alternative splicing

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF110178 mRNA. Translation: AAD28371.1.
AF110179 mRNA. Translation: AAD28372.1.
AF128842 mRNA. Translation: AAD40638.1.
AC074229 Genomic DNA. No translation available.
CH466521 Genomic DNA. Translation: EDK97924.1.
AF068900 mRNA. Translation: AAC19388.1.
AB027140 mRNA. Translation: BAA77688.1.
AF002015 Genomic DNA. Translation: AAC53252.1.
AF159565 mRNA. Translation: AAF00193.1.
CCDSiCCDS28154.1. [Q9QY96-1]
RefSeqiNP_038831.2. NM_013803.3. [Q9QY96-1]
XP_006521792.1. XM_006521729.2. [Q9QY96-1]
XP_006521793.1. XM_006521730.2. [Q9QY96-1]
XP_006521794.1. XM_006521731.3. [Q9QY96-1]
XP_006521795.1. XM_006521732.2. [Q9QY96-1]
UniGeneiMm.103619.
Mm.393142.

3D structure databases

ProteinModelPortaliQ9QY96.
SMRiQ9QY96.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

STRINGi10090.ENSMUSP00000069080.

Chemistry databases

GuidetoPHARMACOLOGYi54.

Protein family/group databases

GPCRDBiSearch...

PTM databases

iPTMnetiQ9QY96.
PhosphoSitePlusiQ9QY96.

Proteomic databases

PaxDbiQ9QY96.
PRIDEiQ9QY96.

Protocols and materials databases

DNASUi12374.
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000063597; ENSMUSP00000069080; ENSMUSG00000051980. [Q9QY96-1]
ENSMUST00000114847; ENSMUSP00000110496; ENSMUSG00000051980. [Q9QY96-2]
ENSMUST00000172826; ENSMUSP00000133500; ENSMUSG00000051980. [Q9QY96-1]
GeneIDi12374.
KEGGimmu:12374.
UCSCiuc007zcp.1. mouse. [Q9QY96-1]
uc012afg.1. mouse. [Q9QY96-2]

Organism-specific databases

CTDi846.
MGIiMGI:1351351. Casr.

Phylogenomic databases

eggNOGiKOG1056. Eukaryota.
ENOG410XR6W. LUCA.
GeneTreeiENSGT00760000118974.
HOVERGENiHBG052876.
InParanoidiQ9QY96.
KOiK04612.
OMAiMGEQVTF.
OrthoDBiEOG091G01NA.
TreeFamiTF331269.

Enzyme and pathway databases

ReactomeiR-MMU-416476. G alpha (q) signalling events.
R-MMU-418594. G alpha (i) signalling events.
R-MMU-420499. Class C/3 (Metabotropic glutamate/pheromone receptors).

Miscellaneous databases

PROiPR:Q9QY96.
SOURCEiSearch...

Gene expression databases

BgeeiENSMUSG00000051980.
CleanExiMM_CASR.
GenevisibleiQ9QY96. MM.

Family and domain databases

InterProiView protein in InterPro
IPR001828. ANF_lig-bd_rcpt.
IPR000337. GPCR_3.
IPR011500. GPCR_3_9-Cys_dom.
IPR017978. GPCR_3_C.
IPR017979. GPCR_3_CS.
IPR028082. Peripla_BP_I.
PfamiView protein in Pfam
PF00003. 7tm_3. 1 hit.
PF01094. ANF_receptor. 1 hit.
PF07562. NCD3G. 1 hit.
PRINTSiPR00248. GPCRMGR.
SUPFAMiSSF53822. SSF53822. 1 hit.
PROSITEiView protein in PROSITE
PS00979. G_PROTEIN_RECEP_F3_1. 1 hit.
PS00980. G_PROTEIN_RECEP_F3_2. 1 hit.
PS00981. G_PROTEIN_RECEP_F3_3. 1 hit.
PS50259. G_PROTEIN_RECEP_F3_4. 1 hit.
ProtoNetiSearch...

Entry informationi

Entry nameiCASR_MOUSE
AccessioniPrimary (citable) accession number: Q9QY96
Secondary accession number(s): G3UX06
, O08968, O88519, Q9QY95, Q9QZU8, Q9R1D6, Q9R1Y2
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 21, 2001
Last sequence update: October 3, 2012
Last modified: May 10, 2017
This is version 140 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. 7-transmembrane G-linked receptors
    List of 7-transmembrane G-linked receptor entries
  2. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.