| Literature References | 1. NUCLEAR RECEPTORS NOMENCLATURE COMMITTEE
A unified nomenclature system for the nuclear receptor superfamily.
CELL 97 161-163 (1999).
2. NISHIKAWA, J-I., KITAURA, M., IMAGAWA, M. AND NISHIHARA, T.
Vitamin D receptor contains multiple dimerisation interfaces that
are functionally different.
NUCLEIC ACIDS RES. 23(4) 606-611 (1995).
3. DE VOS, P., SCHMITT, J., VERHOEVEN, G. AND STUNNENBERG, G.
Human androgen receptor expressed in HeLa cells activates transcription
in vitro.
NUCLEIC ACIDS RES. 22(7) 1161-1166 (1994).
4. LEHMANN, J.M., HOFFMANN, B. AND PFAHL, M.
Genomic organization of the retinoic acid receptor gamma gene.
NUCLEIC ACIDS RES. 19 573-578 (1991).
5. KRUST, A., KASTNER, P., PETKOVICH, M., ZELENT, A. AND CHAMBON, P.
A third human retinoic acid receptor, hRAR-gamma.
PROC.NATL.ACAD.SCI.U.S.A. 86 5310-5314 (1989).
6. RENAUD, J.P., ROCHEL, N., RUFF, M., VIVAT, V., CHAMBON, P.,
GRONEMEYER, H. AND MORAS, D.
Crystal structure of the RAR-gamma ligand-binding domain bound to
all-trans retinoic acid.
NATURE 378 681-689 (1995).
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| Documentation | Steroid or nuclear hormone receptors (NRs) constitute an important super-
family of transcription regulators that are involved in widely diverse
physiological functions, including control of embryonic development, cell
differentiation and homeostasis [1]. Members of the superfamily include the
steroid hormone receptors and receptors for thyroid hormone, retinoids,
1,25-dihydroxy-vitamin D3 and a variety of other ligands. The proteins
function as dimeric molecules in nuclei to regulate the transcription of
target genes in a ligand-responsive manner [2,3]. In addition to C-terminal
ligand-binding domains, these nuclear receptors contain a highly-conserved,
N-terminal zinc-finger that mediates specific binding to target DNA
sequences, termed ligand-responsive elements. In the absence of ligand,
steroid hormone receptors are thought to be weakly associated with nuclear
components; hormone binding greatly increases receptor affinity.
NRs are extremely important in medical research, a large number of them
being implicated in diseases such as cancer, diabetes, hormone resistance
syndromes, etc. [1]. While several NRs act as ligand-inducible transcription
factors, many do not yet have a defined ligand and are accordingly termed
"orphan" receptors. During the last decade, more than 300 NRs have been
described, many of which are orphans, which cannot easily be named due to
current nomenclature confusions in the literature. However, a new system
has recently been introduced in an attempt to rationalise the increasingly
complex set of names used to describe superfamily members [1].
The retinoic acid receptors (RAR) belong to the large family of ligand
responsive gene regulatory proteins that includes receptors for steroid and
thyroid hormones [4]. These proteins contain two highly conserved domains
that are involved in determining their DNA and ligand-binding activities [4].
Three distinct RARs have been identified (termed RAR alpha, beta, and gamma)
and are encoded by genes on separate chromosomes [4]. Additional isoforms
of the receptors have been described, all of which differ in the N-terminal
regions [4]. Comparison of the amino acid sequences of human and mouse RARs
indicates that interspecies conservation in members of the RAR subfamily
(either alpha, beta or gamma) is much higher than conservation of the
receptors within species [5]. These observations indicate that RAR-alpha,
-beta and -gamma may perform specific functions [5]. hRAR-gamma RNA has
been shown to be the predominant RAR RNA species in human skin, suggesting
that hRAR-gamma mediates some of the retinoid effects in this tissue [4].
The crystal structure of the ligand-binding domain (LBD) of the hRAR-gamma
bound to all-trans retinoic acid has been determined to 2.0A resolution [6].
Overall, the fold is similar to that of the human RXR-alpha apo-LBD, except
for the C-terminal portion, which folds back towards the LBD core,
contributing to the hydrophobic ligand pocket and `sealing' its entry site
[6]. A `mouse trap' mechanism is thus proposed, whereby a ligand-induced
conformational transition re-positions the amphipathic alpha-helix of the
activating domain and forms a transcriptionally active receptor [6].
RETNOICACIDR is a 10 element fingerprint that provides a signature for
retinoic acid (RAR) receptors. The fingerprint was derived from an initial
alignment of 12 sequences: the motifs were drawn from conserved regions
spanning virtually the full alignment length, focusing on those sections
that characterise the retinoic acid receptors but distinguish them from
the rest of the steroid hormone receptor superfamily - motif 1 lies towards
the C-terminus of the modulating domain; motifs 2 and 3 lie immediately
C-terminal to the zinc finger domain within the hinge region; and motifs
4-10 span the ligand-binding domain - motif 4 includes helix 2; motif 5
encodes helix 3; motif 6 spans strands 1-3 and helix 6; motif 7 spans the
C-terminal half of helix 8 and helix 9; motif 8 encodes helix 11; motif 9
encodes the C-terminus of helix 12; and motif 10 spans helix 13. Two
iterations on SPTR37_10f were required to reach convergence, at which
point a true set comprising 26 sequences was identified.
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