| Literature References | 1. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Fingerprinting G protein-coupled receptors.
PROTEIN ENG. 7(2) 195-203 (1994).
2. ATTWOOD, T.K. AND FINDLAY, J.B.C.
G protein-coupled receptor fingerprints.
7TM, VOLUME 2, EDS. G.VRIEND AND B.BYWATER (1993).
3. BIRNBAUMER, L.
G proteins in signal transduction.
ANNU.REV.PHARMACOL.TOXICOL. 30 675-705 (1990).
4. CASEY, P.J. AND GILMAN, A.G.
G protein involvement in receptor-effector coupling.
J.BIOL.CHEM. 263(6) 2577-2580 (1988).
5. ATTWOOD, T.K. AND FINDLAY, J.B.C.
Design of a discriminating fingerprint for G protein-coupled receptors.
PROTEIN ENG. 6(2) 167-176 (1993).
6. SAWZDARGO, M., GEORGE, S.R., NGUYEN, T., XU, S., KOLAKOWSKI, L.F. AND
O'DOWD, B.F.
A cluster of four novel human G protein-coupled receptor genes occurring in
close proximity to CD22 gene on chromosome 19q13.1.
BIOCHEM.BIOPHYS.RES.COMMUN. 239 543-547 (1997).
7. BRISCOE, C.P., TADAYYON, M., ANDREWS, J.L., BENSON, W.G., CHAMBERS, J.K.,
EILERT, M.M., ELLIS, C., ELSHOURBAGY, N.A., GOETZ, A.S., MINNICK, D.T.,
MURDOCK, P.R., SAULS, H.R.JR., SHABON, U., SPINAGE, L.D., STRUM, J.C.,
SZEKERES, P.G., TAN, K.B., WAY, J.M., IGNAR, D.M., WILSON, S. AND MUIR, A.I.
The orphan G protein-coupled receptor GPR40 is activated by medium and long
chain fatty acids.
J.BIOL.CHEM. 278 11303-11311 (2003).
8. ITOH, Y., KAWAMATA, Y., HARADA, M., KOBAYASHI, M., FUJII, R., FUKUSUMI, S.,
OGI, K., HOSOYA, M., TANAKA, Y., UEJIMA, H., TANAKA, H., MARUYAMA, M.,
SATOH, R., OKUBO, S., KIZAWA, H., KOMATSU, H., MATSUMURA, F., NOGUCHI, Y.,
SHINOHARA, T., HINUMA, S., FUJISAWA, Y. AND FUJINO, M.
Free fatty acids regulate insulin secretion from pancreatic beta cells
through GPR40.
NATURE 422 173-176 (2003).
|
| Documentation | G protein-coupled receptors (GPCRs) constitute a vast protein family that
encompasses a wide range of functions (including various autocrine,
paracrine 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 rhodopsin-like GPCRs themselves represent a widespread protein family
that includes hormone, neurotransmitter and light receptors, all of which
transduce extracellular signals through interaction with guanine
nucleotide-binding (G) proteins. Although their activating ligands vary
widely in structure and character, the amino acid sequences of the receptors
are very similar and are believed to adopt a common structural framework
comprising 7 transmembrane (TM) helices [3-5].
A cluster of four intronless GPCR genes, sharing significant sequence
similarity with one another, have been identified on human chromosome
19q13.1, downstream from the CD22 gene [6]. The receptors have been named
GPR40, GPR41, GPR42 and GPR43. The GPR42 protein sequence shares more
than 98% amino acid identity with GPR41 and is located on a possible
polymorphic insert [6].
GPR40 has recently been shown to bind long-chain free fatty acids, molecules
that have a role in various cellular processes, including regulation of
insulin secretion [7,8]. Expression of GPR40 is restricted to the pancreas,
with high levels in the islets and pancreatic beta cell lines [8]. Upon
activation, GPR40 appears to couple predominantly to Gq and partially to Gi
proteins, and has been shown to amplify glucose-stimulated insulin secretion
from pancreatic beta cells. The receptor may therefore be a potential target
for anti-diabetic drugs [8].
FATTYACIDR is an 8-element fingerprint that provides a signature for fatty
acid receptor GPR40. The fingerprint was derived from an initial alignment
of 3 sequences: the motifs were drawn from conserved sections within loop
and TM regions, focusing on those areas of the alignment that characterise
the GPR40 fatty acid receptors but distinguish them from the rest of the
GPR40-related family - motif 1 encodes the first cytoplasmic loop, leading
into TM domain 2; motifs 2 and 3 span the first external loop; motif 4 lies
in the second cytoplasmic loop; motif 5 resides in the central portion of
the second external loop; motif 6 is located in the third cytoplasmic loop;
motif 7 encodes part of the third external loop and the N-terminal portion
of TM domain 7; and motif 8 spans the C-terminal portion of TM domain 7. A
single iteration on SPTR40_22f was required to reach convergence, no further
sequences being identified beyond the starting set.
|