| 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. WATSON, S. AND ARKINSTALL, S.
Glycoprotein hormones.
In THE G-PROTEIN-LINKED RECEPTOR FACTSBOOK, ACADEMIC PRESS, 1994, pp142-149.
7. JIANG, X., DREANO, M., BUCKLER, D.R., CHENG, S., YTHIER, A., WU, H.,
HENDRICKSON, W.A. AND EL TAYAR, N.
Structural predictions for the ligand-binding region of glycoprotein hormone
receptors and the nature of hormone-receptor interactions.
STRUCTURE 3 1341-1353 (1995).
8. SHENKER, A., LAUE, L., KOSUGI, S., MERENDINO, J.J. JR., MINEGISHI, T.
AND CUTLER, G.B.
A constitutively activating mutation of the luteinizing hormone receptor in
familial male precocious puberty.
NATURE 365 652-654 (1993).
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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, 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 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].
The gonadotrophins (luteinising hormone, choriogonadotrophin, follicle-
stimulating hormone) and thyroid-stimulating hormone are heterotrimeric
glycoproteins composed of a common alpha-subunit and distinct beta-subunits
[6]. The carbohydrate moiety of the glycoproteins has an essential role in
receptor recognition. The receptors share close sequence similarity, and
are characterised by large extracellular domains believed to be involved
in hormone binding via leucine-rich repeats (LRR) [7]. Modelling of this
portion of the receptors suggests that they contain three-dimensional
structures similar to that of porcine ribonuclease inhibitor [7].
The beta subunits of LH (also known as lupotrophin) and hCG are closely
related in sequence and elicit their biological actions via the same
receptor [6]. LH is released from the anterior pituitary under the
influence of gonadotrophin-releasing hormone and progesterones [6]. CG is
released by the placenta during pregnancy [6]. In females, LH stimulates
ovulation and is the major hormone involved in the regulation of
progesterone secretion by the corpus luteum [6]. In males, it stimulates
Leydig cells to secrete androgens, particularly testosterone. The receptor
is found in organs involved in reproductive physiology, including testicular
Leydig cells, ovarian theca, granulosa, luteal and interstitial cells [6].
The receptor activates adenylyl cyclase through Gs and stimulates the
phosphoinositide pathway through a pertussis-toxin-insensitive G protein [6].
Familial male precocious puberty (FMPP) is a gonadotropin-independent
disorder that is inherited in an autosomal dominant, male-limited pattern
[8]. Affected males generally exhibit signs of puberty by age 4 [8].
Testosterone production and Leydig cell hyperplasia occur in the context of
prepubertal levels of luteinising hormone (LH). FMPP was thought to be due
to a mutant receptor activated in the presence of little or no agonist. A
single A-G base change that results in substitution of glycine for aspartate
at position 578 in LH receptor TM domain 6 was found in affected individuals
from eight different families [8]. Linkage of the mutation to FMPP was
supported by restriction-digest analysis [8]. Further results suggest that
autonomous Leydig cell activity in FMPP is caused by a constitutively
activated LH receptor [8].
LSHRECEPTOR is a 10-element fingerprint that provides a signature for the
lutropin-choriogonadotropic hormone receptors. 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 LH/CG hormone receptors but distinguish
them from the rest of the glycoprotein hormone receptor family - motifs 1-8
reside within the N-terminal half of the alignment, prior to the TM domains;
and motifs 9 and 10 lie at the C-terminus. Two iterations on SPTR37_9f were
required to reach convergence, at which point a true set comprising 8
sequences was identfied.
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