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PR00592

Identifier
CASENSINGR  [View Relations]  [View Alignment]  
Accession
PR00592
No. of Motifs
13
Creation Date
13-AUG-1996  (UPDATE 10-JUN-1999)
Title
Extracellular calcium-sensing receptor signature
Database References
PRINTS; PR90007 7TM; PR90006 GPCRCLAN; PR00248 GPCRMGR

INTERPRO; IPR000068
GCRDB; GCR_1337; GCR_1874; GCR_2012; GCR_2696; GCR_2697; GCR_0900

GCRDB; GCR_1449
Literature References
1. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994). 
 
2. MASU, M., TANABE, Y., TSUCHIDA, K., SHIGEMOTO, R. AND NAKANISHI, S.
Sequence and expression of a metabotropic glutamate receptor.
NATURE 349 760-765 (1991).
 
3. HOUAMED, K.M., KUIJPER, J.L., GILBERT, T.L., HALDEMAN, B.A., OHARA, P.J.,
MULVIHILL, E.R., ALMERS, W. AND HAGEN, F.S.
Cloning, expression and gene structure of a G protein-coupled glutamate
receptor from rat brain.
SCIENCE 252 1318-1321 (1991).
 
4. ABE, T., SUGIHARA, H., NAWA, H., SHIGEMOTO, R., MIZUNO, N. AND 
NAKANISHI, S.
Molecular characterisation of a novel metabotropic glutamate receptor
MGLUR5 coupled to inositol phosphate/Ca2+ signal transduction.
J.BIOL.CHEM. 267(19) 13361-13368 (1992).
 
5. TANABE, Y., MASU, M., ISHII, T., SHIGEMOTO, R. AND NAKANISHI, S.
A family of metabotropic glutamate receptors.
NEURON 8(1) 169-179 (1992).
 
6. BROWN, E.M., GAMBA, G., RICCARDI, D., LOMBARDI, M., BUTTERS, R.,
KIFOR, O., SUN, A., HEDIGER, M.A., LYTTON, J. AND HEBERT, S.C.
Cloning an characterisation of an extracellular Ca(2+)-sensing receptor
from bovine parathyroid.
NATURE 366 575-580 (1993).
 
7. WARD, B.K., STUCKEY, B.G., GUTTERIDGE, D.H., LAING, N.G., PULLAN, P.T.
AND RATAJCZAK, T.
A novel mutation (L174R) in the Ca2+-sensing receptor gene associated with
familial hypocalciuric hypercalcemia.
HUM.MUTAT. 10 233-235 (1997). 
 
8. PEARCE, S.H., TRUMP, D., WOODING, C., BESSER, G.M., CHEW, S.L., GRANT, D.B.,
HEATH, D.A., HUGHES, I.A., PATERSON, C.R. AND WHYTE, M.P.
Calcium-sensing receptor mutations in familial benign hypercalcemia and 
neonatal hyperparathyroidism.
J.CLIN.INVEST. 96 2683-2692 (1995).
 
9. POLLAK, M.R., BROWN, E.M., ESTEP, H.L., MCLAINE, P.N., KIFOR, O.,
PARK, J., HEBERT, S.C., SEIDMAN, C.E. AND SEIDMAN, J.G.
Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene
mutation.
NAT.GENET. 8 303-307 (1994).

Documentation
G protein-coupled receptors (GPCRs) constitute a vast protein family that 
encompasses a wide range of functions (including various autocrine, para-
crine and endocrine processes). They show considerable diversity at the 
sequence level, on the basis of which they can be separated into distinct 
groups. We use the term clan to describe the GPCRs, as they embrace a group
of families for which there are indications of evolutionary relationship, 
but between which there is no statistically significant similarity in 
sequence [1]. The currently known clan members include the rhodopsin-like 
GPCRs, the secretin-like GPCRs, the cAMP receptors, the fungal mating
pheromone receptors, and the metabotropic glutamate receptor family.
 
The metabotropic glutamate receptors are functionally and pharmacologically
distinct from the ionotropic glutamate receptors. They are coupled to G-
proteins and stimulate the inositol phosphate/Ca2+ intracellular signalling 
pathway [2-5]. The amino acid sequences of the receptors contain high
proportions of hydrophobic residues grouped into 7 domains, in a manner
reminiscent of the rhodopsins and other receptors believed to interact with
G proteins. However, while a similar 3D framework has been proposed to
account for this, there is no significant sequence identity between these
and receptors of the rhodopsin-type family: the metabotropic glutamate
receptors thus bear their own distinctive `7TM' signature. 
 
The calcium-sensing receptor (CaSR) is an integral membrane protein that
senses changes in the extracellular concentration of calcium ions. The 
activity of the receptor is mediated by a G protein that activates a 
phosphatidyl-inositol-calcium second messenger system. The sequences of the
receptors show a high degree of similarity to the TM signature that
characterises the metabotropic glutamate receptors. In addition, the
sequences contain a large extracellular domain that includes clusters of
acidic amino acid residues, which may be involved in calcium binding [6].
 
Defects in CaSR that result in reduced activity of the receptor cause
familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperpara-
thyroidism (NSHPT), inherited conditions characterised by altered calcium
homeostasis [7,8]. FHH-affected individuals exhibit mild or modest hyper-
calcemia, relative hypocalciuria and inappropriately normal PTH levels. By
contrast, NSHPT is a rare autosomal recessive life-threatening disorder 
characterised by high serum calcium concentrations, skeletal demineral-
isation and parathyroid hyperplasia. In addition, defects resulting from
receptor activation at subnormal Ca(2+) levels cause autosomal dominant
hypocalcemia [9].
 
CASENSINGR is a 13-element fingerprint that provides a signature for the 
calcium-sensing receptors. The fingerprint was derived from an initial
alignment of 6 sequences: the motifs were drawn from conserved regions
spanning the full alignment length, focusing on those sections that
characterise the calcium-sensing receptors but distinguish them from the
rest of the metabotropic receptor superfamily - motifs 1-11 lie in the
N-terminal extracellular domain; motif 12 resides in the second cytoplasmic
loop, between putative TM domains 3 and 4; and motif 13 lies in the 
C-terminal cytoplasmic domain. A single iteration on OWL31.1 was required 
to reach convergence, no further sequences being identified beyond the 
starting set. Several partial matches were found, all of which are fragments
and calcium-sensing receptor homologues that match 2 motifs.
 
An update on SPTR37_9f identified a true set of 4 sequences, and 5
partial matches.
Summary Information
   4 codes involving 13 elements
0 codes involving 12 elements
0 codes involving 11 elements
0 codes involving 10 elements
0 codes involving 9 elements
0 codes involving 8 elements
0 codes involving 7 elements
0 codes involving 6 elements
0 codes involving 5 elements
0 codes involving 4 elements
0 codes involving 3 elements
4 codes involving 2 elements
Composite Feature Index
134444444444444
120000000000000
110000000000000
100000000000000
90000000000000
80000000000000
70000000000000
60000000000000
50000000000000
40000000000000
30000000000000
21100300300000
12345678910111213
True Positives
CASR_BOVIN    CASR_HUMAN    CASR_RAT      O73635        
True Positive Partials
Codes involving 2 elements
O70410 O73636 O93552 Q99934
Sequence Titles
CASR_BOVIN  EXTRACELLULAR CALCIUM-SENSING RECEPTOR PRECURSOR (CASR) (PARATHYROID CELL CALCIUM-SENSING RECEPTOR) - Bos taurus (Bovine). 
CASR_HUMAN EXTRACELLULAR CALCIUM-SENSING RECEPTOR PRECURSOR (CASR) (PARATHYROID CELL CALCIUM-SENSING RECEPTOR) - Homo sapiens (Human).
CASR_RAT EXTRACELLULAR CALCIUM-SENSING RECEPTOR PRECURSOR (CASR) (PARATHYROID CELL CALCIUM-SENSING RECEPTOR) - Rattus norvegicus (Rat).
O73635 CALCIUM2+ SENSING RECEPTOR - Fugu rubripes (Japanese pufferfish) (Takifugu rubripes).

O70410 PUTATIVE PHEROMONE RECEPTOR V2R2 - Mus musculus (Mouse).
O73636 PHEROMONE RECEPTOR - Fugu rubripes (Japanese pufferfish) (Takifugu rubripes).
O93552 PUTATIVE ODORANT RECEPTOR - Carassius auratus (Goldfish).
Q99934 CALCIUM-SENSING RECEPTOR ISOFORM B - HOMO SAPIENS (HUMAN).
Scan History
OWL28_1    1  20   NSINGLE    
OWL31_1 1 100 NSINGLE
SPTR37_9f 2 86 NSINGLE
Initial Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
WHSSAYGPDQRAQKKG CASR_RAT 15 15 -
WHTSAYGPDQRAQKKG CASR_HUMAN 15 15 -
WCTSAYGPDQRAQKKG CASR_BOVIN 16 16 -
WHTSAYGPDQRAQKKG HUMCASR 15 15 -
WHTSAYGPDQRAQKKG B56715 15 15 -
YVISTYGPNQRAQMTG AB008857 16 16 -

Motif 2 width=17
Element Seqn Id St Int Rpt
FGVAAKDQDLKSRPESV CASR_RAT 42 11 -
FGVAAKDQDLKSRPESV CASR_HUMAN 42 11 -
FGVAVKDQDLKSRPESV CASR_BOVIN 43 11 -
FGVAAKDQDLKSRPESV HUMCASR 42 11 -
FGVAAKDQDLKSRPESV B56715 42 11 -
FGISSKDENLAARPEST AB008857 43 11 -

Motif 3 width=16
Element Seqn Id St Int Rpt
VAQNKIDSLNLDEFCN CASR_RAT 115 56 -
VAQNKIDSLNLDEFCN B56715 115 56 -
VAQNKIDSLNLDEFCN AB008857 116 56 -
VAQNKIDSLNLDEFCN HUMCASR 115 56 -
VAQNKIDSLNLDEFCN CASR_HUMAN 115 56 -
VAQNKIDSLNLDEFCN CASR_BOVIN 116 56 -

Motif 4 width=14
Element Seqn Id St Int Rpt
NCSEHIPSTIAVVG HUMCASR 130 -1 -
NCSEHIPSTIAVVG B56715 130 -1 -
NCTDHIPATIAVVG AB008857 131 -1 -
NCSEHIPSTIAVVG CASR_BOVIN 131 -1 -
NCSEHIPSTIAVVG CASR_HUMAN 130 -1 -
NCSEHIPSTIAVVG CASR_RAT 130 -1 -

Motif 5 width=22
Element Seqn Id St Int Rpt
DDDYGRPGIEKFREEAEERDIC CASR_RAT 215 71 -
DDDYGRPGIEKFREEAEERDIC CASR_HUMAN 215 71 -
DDDYGRPGIEKFREEAEERDIC CASR_BOVIN 216 71 -
DDDYGRPGIEKFEKEMEERDIC AB008857 216 71 -
DDDYGRPGIEKFREEAEERDIC B56715 215 71 -
DDDYGRPGIEKFREEAEERDIC HUMCASR 215 71 -

Motif 6 width=24
Element Seqn Id St Int Rpt
ELISQYFEDCEIKALVDRIENSTA AB008857 242 4 -
ELISQYSDEEEIQHVVEVIQNSTA B56715 241 4 -
ELISQYSDEEEIQHVVEVIQNSTA HUMCASR 241 4 -
ELISQYSDEEEIQQVVEVIQNSTA CASR_RAT 241 4 -
ELISQYSDEEEIQHVVEVIQNSTA CASR_HUMAN 241 4 -
ELISQYSDEEKIQQVVEVIQNSTA CASR_BOVIN 242 4 -

Motif 7 width=16
Element Seqn Id St Int Rpt
EPLIKEMVRRNITDRI AB008857 278 12 -
EPLIKEIVRRNITGKI B56715 277 12 -
EPLIKEIVRRNITGKI HUMCASR 277 12 -
EPLIKEIVRRNITGRI CASR_RAT 277 12 -
EPLIKEIVRRNITGKI CASR_HUMAN 277 12 -
EPLIKEIVRRNITGRI CASR_BOVIN 278 12 -

Motif 8 width=19
Element Seqn Id St Int Rpt
VVGGTIGFALKAGQIPGFR HUMCASR 313 20 -
VVGGTIGFALKAGQIPGFR CASR_HUMAN 313 20 -
VVGGTIGFGLKAGQIPGFR CASR_BOVIN 314 20 -
VVEGTIGFVLKAGNIPGFR AB008857 314 20 -
VVGGTIGFALKAGQIPGFR B56715 313 20 -
VVGGTIGFGLKAGQIPGFR CASR_RAT 313 20 -

Motif 9 width=18
Element Seqn Id St Int Rpt
RGLFTNGSCADIKKVEAW CASR_RAT 441 109 -
RGLFTNGSCADIKKVEAW B56715 441 109 -
HGLFANNSCADIKKMEAW AB008857 427 94 -
RGLFTNGSCADIKKVEAW CASR_BOVIN 442 109 -
RGLFTNGSCADIKKVEAW CASR_HUMAN 441 109 -
RGLFTNGSCADIKKVEAW HUMCASR 441 109 -

Motif 10 width=21
Element Seqn Id St Int Rpt
KEVGYYNVYAKKGERLFINEE CASR_RAT 506 47 -
KEVGYYNVYAKKGERLFINEE CASR_HUMAN 506 47 -
KEVGYYNVYAKKGERLFINDE CASR_BOVIN 507 47 -
REVGYYHMHARRGAKLLIDNT AB008857 492 47 -
KEVGYYNVYAKKGERLFINEE HUMCASR 506 47 -
KEVGYYNVYAKKGERLFINEE B56715 506 47 -

Motif 11 width=15
Element Seqn Id St Int Rpt
DGEYSGETDASACDK CASR_RAT 570 43 -
DGEYSDHKDASICTK AB008857 556 43 -
DGEYSDETDASACNK B56715 580 53 -
DGEYSDETDASACNK HUMCASR 570 43 -
DGEYSDETDASACDK CASR_BOVIN 571 43 -
DGEYSDETDASACNK CASR_HUMAN 570 43 -

Motif 12 width=19
Element Seqn Id St Int Rpt
EAKIPTSIHRKWWGLNLQF AB008857 693 122 -
EAKIPTSFHRKWWGLNLQF CASR_RAT 707 122 -
EAKIPTSFHRKWWGLNLQF CASR_HUMAN 707 122 -
EAKIPTSFHRKWWGLNLQF CASR_BOVIN 708 122 -
EAKIPTSFHRKWWGLNLQF HUMCASR 707 122 -
EAKIPTSFHRKWWGLNLQF B56715 717 122 -

Motif 13 width=23
Element Seqn Id St Int Rpt
PSRNTIEEVRCSTAAHAFKVAAR CASR_BOVIN 865 138 -
PSRNTIEEVRCSTAAHAFKVAAR B56715 874 138 -
PSRNTIEEVRCSTARHAFKVAAR HUMCASR 864 138 -
PSRNTIEEVRSSTAAHAFKVAAR CASR_RAT 864 138 -
PSRNTIEEVRCSTAAHAFKVAAR CASR_HUMAN 864 138 -
PCRNTIEEVRCSTAAHAFRVAAK AB008857 849 137 -
Final Motifs
Motif 1  width=16
Element Seqn Id St Int Rpt
WCTSAYGPDQRAQKKG CASR_BOVIN 16 16 -
WHTSAYGPDQRAQKKG CASR_HUMAN 15 15 -
WHSSAYGPDQRAQKKG CASR_RAT 15 15 -
YVISTYGPNQRAQMTG O73635 16 16 -

Motif 2 width=17
Element Seqn Id St Int Rpt
FGVAVKDQDLKSRPESV CASR_BOVIN 43 11 -
FGVAAKDQDLKSRPESV CASR_HUMAN 42 11 -
FGVAAKDQDLKSRPESV CASR_RAT 42 11 -
FGISSKDENLAARPEST O73635 43 11 -

Motif 3 width=16
Element Seqn Id St Int Rpt
VAQNKIDSLNLDEFCN CASR_BOVIN 116 56 -
VAQNKIDSLNLDEFCN CASR_HUMAN 115 56 -
VAQNKIDSLNLDEFCN CASR_RAT 115 56 -
VAQNKIDSLNLDEFCN O73635 116 56 -

Motif 4 width=14
Element Seqn Id St Int Rpt
NCSEHIPSTIAVVG CASR_BOVIN 131 -1 -
NCSEHIPSTIAVVG CASR_HUMAN 130 -1 -
NCSEHIPSTIAVVG CASR_RAT 130 -1 -
NCTDHIPATIAVVG O73635 131 -1 -

Motif 5 width=22
Element Seqn Id St Int Rpt
DDDYGRPGIEKFREEAEERDIC CASR_BOVIN 216 71 -
DDDYGRPGIEKFREEAEERDIC CASR_HUMAN 215 71 -
DDDYGRPGIEKFREEAEERDIC CASR_RAT 215 71 -
DDDYGRPGIEKFEKEMEERDIC O73635 216 71 -

Motif 6 width=24
Element Seqn Id St Int Rpt
ELISQYSDEEKIQQVVEVIQNSTA CASR_BOVIN 242 4 -
ELISQYSDEEEIQHVVEVIQNSTA CASR_HUMAN 241 4 -
ELISQYSDEEEIQQVVEVIQNSTA CASR_RAT 241 4 -
ELISQYFEDCEIKALVDRIENSTA O73635 242 4 -

Motif 7 width=16
Element Seqn Id St Int Rpt
EPLIKEIVRRNITGRI CASR_BOVIN 278 12 -
EPLIKEIVRRNITGKI CASR_HUMAN 277 12 -
EPLIKEIVRRNITGRI CASR_RAT 277 12 -
EPLIKEMVRRNITDRI O73635 278 12 -

Motif 8 width=19
Element Seqn Id St Int Rpt
VVGGTIGFGLKAGQIPGFR CASR_BOVIN 314 20 -
VVGGTIGFALKAGQIPGFR CASR_HUMAN 313 20 -
VVGGTIGFGLKAGQIPGFR CASR_RAT 313 20 -
VVEGTIGFVLKAGNIPGFR O73635 314 20 -

Motif 9 width=18
Element Seqn Id St Int Rpt
RGLFTNGSCADIKKVEAW CASR_BOVIN 442 109 -
RGLFTNGSCADIKKVEAW CASR_HUMAN 441 109 -
RGLFTNGSCADIKKVEAW CASR_RAT 441 109 -
HGLFANNSCADIKKMEAW O73635 427 94 -

Motif 10 width=21
Element Seqn Id St Int Rpt
KEVGYYNVYAKKGERLFINDE CASR_BOVIN 507 47 -
KEVGYYNVYAKKGERLFINEE CASR_HUMAN 506 47 -
KEVGYYNVYAKKGERLFINEE CASR_RAT 506 47 -
REVGYYHMHARRGAKLLIDNT O73635 492 47 -

Motif 11 width=15
Element Seqn Id St Int Rpt
DGEYSDETDASACDK CASR_BOVIN 571 43 -
DGEYSDETDASACNK CASR_HUMAN 570 43 -
DGEYSGETDASACDK CASR_RAT 570 43 -
DGEYSDHKDASICTK O73635 556 43 -

Motif 12 width=19
Element Seqn Id St Int Rpt
EAKIPTSFHRKWWGLNLQF CASR_BOVIN 708 122 -
EAKIPTSFHRKWWGLNLQF CASR_HUMAN 707 122 -
EAKIPTSFHRKWWGLNLQF CASR_RAT 707 122 -
EAKIPTSIHRKWWGLNLQF O73635 693 122 -

Motif 13 width=23
Element Seqn Id St Int Rpt
PSRNTIEEVRCSTAAHAFKVAAR CASR_BOVIN 865 138 -
PSRNTIEEVRCSTAAHAFKVAAR CASR_HUMAN 864 138 -
PSRNTIEEVRSSTAAHAFKVAAR CASR_RAT 864 138 -
PCRNTIEEVRCSTAAHAFRVAAK O73635 849 137 -