Nuclear receptor coregulators

Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of nuclear receptor coregulators can be found at the Nuclear Receptor Signaling Atlas website. Nuclear receptor coregulators are a class of transcription coregulators that have been shown to be involved in any aspect of signaling by any member of the nuclear receptor superfamily. A comprehensive database of nuclear receptor coregulators can be found at the Nuclear Receptor Signaling Atlas website. The ability of nuclear receptors to alternate between activation and repression in response to specific molecular cues, is now known to be attributable in large part to a diverse group of cellular factors, collectively termed coregulators and including coactivators and corepressors. The study of nuclear receptors owed a debt to decades of historical endocrinology and pathology, and prior to their discovery there was a wealth of empirical evidence that suggested their existence. Coregulators, in contrast, have been the subject of a rapid accumulation of functional and mechanistic data which is yet to be consolidated into an integrated picture of their biological functions. While this article refers to the historical terms 'coactivator' and 'corepressor' it should be noted that this distinction is less clear than was at first thought, and it is now known that cell type, cell signaling state and promoter identity can influence the direction of action of any given coregulator. Coregulators are often incorrectly referred to as cofactors, which are small, non-protein molecules required by an enzyme for full activity, e.g. NAD+. See also coactivators As far back as the early 1970s, receptor-associated nonhistone proteins were known to support the function of nuclear receptors. In the early 1990s, some investigators such as Keith Yamamoto had suggested a role for non-DNA nuclear acceptor molecules. A biochemical strategy designed in Myles Brown's laboratory provided the first direct evidence of ligand-dependent recruitment by nuclear receptors of ancillary molecules. The yeast two-hybrid protein-protein interaction assay led to the identification of an array of receptor-interacting factors in David Moore's laboratory and RIP140 repressive protein was discovered in Malcolm Parker's laboratory. The stage was now set for the cloning of the coactivators. The first authentic, common nuclear receptor coactivator was steroid receptor coactivator 1, or SRC-1, first cloned in Bert O’Malley's laboratory. SRC-1 and two related proteins, GRIP-1, cloned first by Michael Stallcup, and ACTR/p/CIP, initially identified in Ron Evans and Geoff Rosenfeld's lab, together make up the SRC family of coactivators. The SRC family is defined by the presence in the N-terminus of tandem PAS and beta-HLH motifs; a centrally-located domain which binds the coactivators CBP and p300; and a C-terminal region which mediates interaction with the CARM-1 coactivator. Malcolm Parker's laboratory was the first to show that a recurring structural feature of many coactivators is an alpha-helical LXXLL motif (a contiguous sequence of 5 amino acids where L = leucine and X = any amino acid), or nuclear receptor box, present from a single to several copies in many coactivators, which is implicated in their ligand-dependent recruitment by the receptor AF-2. The SRC coactivator family, for example, has a conserved cluster of NR boxes located in the central region of each member of the family.