Nuclear receptor superfamily: Principles of signaling
P. Germain, L. Altucci, W. Bourguet, C. Rochette-Egly, and H. Gronemeyer
1 IGBMC -B.P.10142, F-67404 Illkirch Cedex, C.U.de Strasbourg,
France;
2 Dipartimento di Patologia Generale, Seconda Università di Napoli,
Vico Luigi DeCrecchio 7, I-80138 Napoli, Italia;
3 CBS,CNRS U5048-INSERM U554,15 av.C. Flahault, F-34039 Montpellier,
France
Abstract: Nuclear receptors (NRs) comprise a family of 49 members
that share a common structural organization and act as ligand-inducible
transcription factors with major (patho)physiological impact. For some
NRs (orphan receptors), cognate ligands have not yet been
identified or may not exist. The principles of DNA recognition and ligand
binding are well understood from both biochemical and crystal structure
analyses. The 3D structures of several DNA-binding domains (DBDs),in
complexes with a variety of cognate response elements, and multiple
ligand-binding domains (LBDs), in the absence (apoLBD)and presence (holoLBD)
of agonist, have been established and reveal canonical structural organization.
Agonist binding induces a structural transition in the LBD whose most
striking feature is the relocation of helix H12, which is required for
establishing a coactivator complex, through interaction with members
of the p160 family (SRC1, TIF2, AIB1) and/or the TRAP/DRIP complex.
The p160-dependent coactivator complex is a multiprotein complex that
comprises histone acetyltransferases (HATs), such as CBP,methyltransferases,
such as CARM1, and other enzymes (SUMO ligase,etc.). The agonist-dependent
recruitment of the HAT complex results in chromatin modification in
the environment of the target gene promoters, which is requisite to,
or may in some cases be sufficient for, transcription activation. In
the absence of ligands, or in the presence of some antagonists, certain
NRs are bound to distinct multiprotein complexes through the interaction
with corepressors, such as NCoR and SMRT. Corepressor complexes comprise
histone deacetylases (HDACs) that have the capacity to condense chromatin
over target gene promoters. Ligands have been designed that selectively
modulate the interaction between NRs and their coregulators. Both HATs
and HDACs can also modify the acetylation status of nonhistone proteins,
but the significance in the context of NR signaling is unclear. NRs
communicate with other intracellular signaling pathways on a mutual
basis, and their functionality may be altered, positively or negatively,
by post-translational modification. The majority of NRs act as retinoid
X receptor (RXR) heterodimers in which RXR cannot a priori respond autonomously
to its cognate ligand to activate target gene transcription. This RXR
subordination allows signaling pathway identity for the RXR partner.
The corresponding mechanism is understood and reveals cell and NR selectivity,
indicating that RXR can, under certain conditions, act autonomously.
NRs are regulators of cell life and death,and NR malfunction can be
at the basis of both disease and therapy, as is impressively documented
in the case of acute promyelocytic leukemia. Recently, several pathways
have been uncovered that link NR action with cell proliferation and
apoptosis.
*Report from a SCOPE/IUPAC project: Implication of Endocrine Active Substances for Human and Wildlife (J. Miyamoto and
J.Burger, editors). Other reports are published in this issue, pp. 1617-2615.