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PR01353

Identifier
GLUCAGNFAMLY  [View Relations]  [View Alignment]  
Accession
PR01353
No. of Motifs
4
Creation Date
06-MAY-2000
Title
Glucagon family receptor signature
Database References
PRINTS; PR01355 GLUCAGNLIKER; PR01354 GLUCAGONR
GCRDB; GCR_2593; GCR_0370; GCR_0771; GCR_0833; GCR_2057; GCR_2059

GCRDB; GCR_0772; GCR_0881; GCR_1272; GCR_1627; GCR_0539; GCR_0540

GCRDB; GCR_0657; GCR_1464
Literature References
1. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994). 
 
2. ISHIHARA T., NAKAMURA S., KAZIRO, Y., TAKAHASHI, T., TAKAHASHI, K.
AND NAGATA, S.
Molecular cloning and expression of a cDNA encoding the secretin receptor
EMBO J. 10 1635-1641 (1991).
 
3. LIN, H.Y., HARRIS, T.L., FLANNERY, M.S., ARUFFO, A., KAJI, E.H., 
GORN, A., KOLAKOWSKI, L.F., LODISH, H.F. AND GOLDRING, S.R.
Expression cloning of adenylate cyclase-coupled calcitonin receptor
SCIENCE 254 1022-1024 (1991).
 
4. JUEPPNER, H., ABOU-SAMRA, A.-B., FREEMAN, M., KONG, X.F., 
SCHIPANI, E., RICHARDS, J., KOLALOWSKI, L.F., HOCK, J., POTTS, J.T.,
KRONENBERG, H.M. AND SEGRE, G.E.
A G protein linked receptor for parathyroid hormone and parathyroid
hormone-related peptide.
SCIENCE 254 1024-1026 (1991).
 
5. ISHIHARA, T., SHIGEMOTO, R., MORI, K., TAKAHASHI, K. AND NAGATA, S.
Functional expression and tissue distribution of a novel receptor for
vasoactive intestinal polypeptide.
NEURON 8(4) 811-819 (1992).
 
6. BURCELIN, R., LI, J. AND CHARRON, M.J.
Cloning and sequence analysis of the murine glucagon receptor-encoding gene. 
GENE 164 305-310 (1995).
 
7. JELINEK, L.J., LOK, S., ROSENBERG, G.B., SMITH, R.A., GRANT, F.J.,
BIGGS, S., BENSCH, P.A., KUIJPER, J.L., SHEPPARD, P.O., SPRECHER, C.A.
Expression cloning and signaling properties of the rat glucagon receptor. 
SCIENCE 259 1614-1616 (1993). 
 
8. VAN EYLL, B., LANKAT-BUTTGEREIT, B., BODE, H.P., GOKE, R. AND GOKE, B.
Signal transduction of the GLP-1-receptor cloned from a human insulinoma. 
FEBS LETT. 348 7-13 (1994).
 
9. WEI, Y. AND MOJSOV, S.
Tissue-specific expression of the human receptor for glucagon-like
peptide-I: brain, heart and pancreatic forms have the same deduced amino
acid sequences.
FEBS LETT. 358 219-224 (1995).  
 
10. THORENS, B.
Expression cloning of the pancreatic beta cell receptor for the gluco- 
incretin hormone glucagon-like peptide 1.
PROC.NATL.ACAD.SCI.U.S.A. 89 8641-8645 (1992). 

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 secretin-like GPCRs include secretin [2], calcitonin [3], parathyroid
hormone/parathyroid hormone-related peptides [4] and vasoactive intestinal
peptide [5], all of which activate adenylyl cyclase and the phosphatidyl-
inositol-calcium pathway. 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 inter-
act with G proteins. However, while a similar 3D framework has been
proposed to account for this, there is no significant sequence similarity
between these families: the secretin-like receptors thus bear their own
unique `7TM' signature.
 
The glucagon receptor (GR) plays a central role in regulating the level of
blood glucose by controlling the rate of hepatic glucose production and 
insulin secretion [6]. GR is expressed predominantly in liver, kidney, 
adrenal, lung and stomach, with lower levels of expression detected in
brown and white adipose tissue, cerebellum, duodenum and heart [6]. Their
role in the control of blood glucose concentrations makes glucagon and GR
especially important to studies of diabetes, in which the loss of control
over blood glucose concentrations clinically defines the disease [7]. GR is
similar to the secretin-like receptor superfamily. It can transduce signals
leading to the accumulation of two different second messengers - i.e., both
cAMP and calcium [7]. 
 
Glucagon-like peptide-1 (GLP-1), which is encoded by the glucagon gene and
released from the gut in response to nutrients, is a potent stimulator of
glucose-induced insulin secretion and proinsulin gene expression of
pancreatic beta-cells [8,9]. In humans, GLP-I exerts its physiological
effect as an incretin. Patients with insulinoma tumors show uncontrolled 
insulin hypersecretion [8]. The GLP-I receptor binds GLP-1 with high 
affinity and couples to activation of adenylate cyclase [10]. The receptor
specifically binds GLP-1 and not peptides of related structure and function,
such as glucagon, gastric inhibitory peptide, VIP or secretin [10]. It is
thought that GLP-I might have effects beyond the pancreas, including the 
cardiovascular and central nervous systems, where a receptor with the same
ligand-binding specificity is found [9].  
 
GLUCAGNFAMLY is a 4-element fingerprint that provides a signature for the
glucagon family of secretin-like GPCRs. The fingerprint was derived from an
initial alignment of 6 sequences: the motifs were drawn from conserved 
regions spanning virtually the full alignment length, focusing on those
sections that characterise the glucagon receptor family but distinguish
them from the rest of the secretin-like GPCR superfamily - motifs 1-3 span
the N-terminal putative extracellular domain; and motif 4 spans the third
extracellular loop. A single iteration on SPTR37_10f was required to reach
convergence, no further sequences being identified beyond the starting set.
Summary Information
6 codes involving  4 elements
0 codes involving 3 elements
0 codes involving 2 elements
Composite Feature Index
46666
30000
20000
1234
True Positives
GLPR_HUMAN    GLPR_MOUSE    GLPR_RAT      GLR_HUMAN     
GLR_MOUSE GLR_RAT
Sequence Titles
GLPR_HUMAN  GLUCAGON-LIKE PEPTIDE 1 RECEPTOR PRECURSOR (GLP-1 RECEPTOR) (GLP-1-R) - HOMO SAPIENS (HUMAN). 
GLPR_MOUSE GLUCAGON-LIKE PEPTIDE 1 RECEPTOR PRECURSOR (GLP-1 RECEPTOR) (GLP-1-R) - MUS MUSCULUS (MOUSE).
GLPR_RAT GLUCAGON-LIKE PEPTIDE 1 RECEPTOR PRECURSOR (GLP-1 RECEPTOR) (GLP-1-R) - RATTUS NORVEGICUS (RAT).
GLR_HUMAN GLUCAGON RECEPTOR PRECURSOR (GL-R) - HOMO SAPIENS (HUMAN).
GLR_MOUSE GLUCAGON RECEPTOR PRECURSOR (GL-R) - MUS MUSCULUS (MOUSE).
GLR_RAT GLUCAGON RECEPTOR PRECURSOR (GL-R) - RATTUS NORVEGICUS (RAT).
Scan History
SPTR37_10f 1  60   NSINGLE    
Initial Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
LLLLGAVGRAGPRP GLPR_MOUSE 12 12 -
LLLLGAVGRAGPRP GLPR_RAT 12 12 -
LLLLLVLSCLPEAP GLR_MOUSE 12 12 -
LLLLVVLSCLPKAP GLR_RAT 12 12 -
LLLLGMVGRAGPRP GLPR_HUMAN 12 12 -
LLLLLLLACQPQVP GLR_HUMAN 11 11 -

Motif 2 width=18
Element Seqn Id St Int Rpt
QKWREYRRQCQHFLTEAP GLPR_MOUSE 37 11 -
QKWREYRHQCQRFLTEAP GLPR_RAT 37 11 -
EKWKLYSDQCHHNLSLLP GLR_MOUSE 35 9 -
EKWKLYSDQCHHNLSLLP GLR_RAT 35 9 -
QKWREYRRQCQRSLTEDP GLPR_HUMAN 37 11 -
EKWKLYGDQCHHNLSLLP GLR_HUMAN 34 9 -

Motif 3 width=12
Element Seqn Id St Int Rpt
PDGPPGSFVNVS GLPR_MOUSE 73 18 -
PDGPPGSFVNVS GLPR_RAT 73 18 -
PDTPPNTTANIS GLR_MOUSE 70 17 -
PDTPPNTTANIS GLR_RAT 70 17 -
PDGEPGSFVNVS GLPR_HUMAN 73 18 -
PDTPANTTANIS GLR_HUMAN 69 17 -

Motif 4 width=17
Element Seqn Id St Int Rpt
FVMDEHARGTLRFIKLF GLPR_MOUSE 369 284 -
FVMDEHARGTLRFVKLF GLPR_RAT 369 284 -
FVTDEHAQGTLRSTKLF GLR_MOUSE 368 286 -
FVTDEHAQGTLRSTKLF GLR_RAT 368 286 -
FVMDEHARGTLRFIKLF GLPR_HUMAN 369 284 -
FVTDEHAQGTLRSAKLF GLR_HUMAN 367 286 -
Final Motifs
Motif 1  width=14
Element Seqn Id St Int Rpt
LLLLGAVGRAGPRP GLPR_MOUSE 12 12 -
LLLLGAVGRAGPRP GLPR_RAT 12 12 -
LLLLLVLSCLPEAP GLR_MOUSE 12 12 -
LLLLVVLSCLPKAP GLR_RAT 12 12 -
LLLLGMVGRAGPRP GLPR_HUMAN 12 12 -
LLLLLLLACQPQVP GLR_HUMAN 11 11 -

Motif 2 width=18
Element Seqn Id St Int Rpt
QKWREYRRQCQHFLTEAP GLPR_MOUSE 37 11 -
QKWREYRHQCQRFLTEAP GLPR_RAT 37 11 -
EKWKLYSDQCHHNLSLLP GLR_MOUSE 35 9 -
EKWKLYSDQCHHNLSLLP GLR_RAT 35 9 -
QKWREYRRQCQRSLTEDP GLPR_HUMAN 37 11 -
EKWKLYGDQCHHNLSLLP GLR_HUMAN 34 9 -

Motif 3 width=12
Element Seqn Id St Int Rpt
PDGPPGSFVNVS GLPR_MOUSE 73 18 -
PDGPPGSFVNVS GLPR_RAT 73 18 -
PDTPPNTTANIS GLR_MOUSE 70 17 -
PDTPPNTTANIS GLR_RAT 70 17 -
PDGEPGSFVNVS GLPR_HUMAN 73 18 -
PDTPANTTANIS GLR_HUMAN 69 17 -

Motif 4 width=17
Element Seqn Id St Int Rpt
FVMDEHARGTLRFIKLF GLPR_MOUSE 369 284 -
FVMDEHARGTLRFVKLF GLPR_RAT 369 284 -
FVTDEHAQGTLRSTKLF GLR_MOUSE 368 286 -
FVTDEHAQGTLRSTKLF GLR_RAT 368 286 -
FVMDEHARGTLRFIKLF GLPR_HUMAN 369 284 -
FVTDEHAQGTLRSAKLF GLR_HUMAN 367 286 -