| 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. HSU, S.Y., NAKABAYASHI, K., NISHI, S., KUMAGAI, J., KUDO, M.,
SHERWOOD, O.D. AND HSUEH, A.J.W.
Activation of orphan receptors by the hormone relaxin.
SCIENCE 295 671-674 (2002).
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| 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].
Relaxin has diverse actions in the reproductive tract and in other tissues
during pregnancy [6]. Although binding sites for relaxin have been found in
reproductive tissue, the nature of the receptor was previously unknown.
Recently, two orphan GPCRs, LGR7 and LGR8, have been identified as receptors
for the hormone. These two receptors contain large extracellular N-termini
with leucine-rich repeat regions, and are structurally similar to the
gonadotropin and thyrotropin receptors [6]. LGR7 is expressed in the brain,
kidney, testis, placenta, uterus, ovary, adrenal gland, prostate, skin and
heart, while LGR8 is expressed mainly in the brain, kidney, muscle, testis,
thyroid, uterus, peripheral blood cells and bone marrow [6]. Upon binding to
LGR7 or 8, relaxin stimulates a dose-dependent increase in cyclic AMP
production, indicating coupling of the receptors to Gs proteins [6].
RELAXINR is a 7-element fingerprint that provides a signature for the
relaxin receptor family. The fingerprint was derived from an initial
alignment of 3 sequences: the motifs were drawn from conserved sections
within external loop and N-terminal regions, focusing on those areas of the
alignment that characterise the relaxin receptors but distinguish them from
the rest of the rhodopsin-like superfamily - motifs 1-4 are located in the
large N-terminal domain; motif 5 lies in the N-terminal portion of the first
external loop; motif 6 resides within the second external loop; and motif 7
spans the final external loop. A single iteration on SPTR40_20f was required
to reach convergence, no further sequences being identified beyond the
starting set. A single partial match was found, GPCR_LYMST, the pond snail
GPCR, which closely resembles the relaxin receptors.
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