An Evolving Understanding of Nuclear Receptor Coregulator Proteins

C J MILLARD and others Nuclear receptor coregulators 51:3 T23–T36 Thematic Review An evolving understanding of nuclear receptor coregulator proteins Correspondence Christopher J Millard, Peter J Watson, Louise Fairall and John W R Schwabe should be addressed to J W R Schwabe Henry Wellcome Laboratories of Structural Biology, Department of Biochemistry, University of Leicester, Email Leicester LE1 9HN, UK [email protected] Abstract Nuclear receptors are transcription factors that regulate gene expression through the Key Words ligand-controlled recruitment of a diverse group of proteins known as coregulators. Most " nuclear receptors nuclear receptor coregulators function in large multi-protein complexes that modify " coregulator complexes chromatin and thereby regulate the transcription of target genes. Structural and functional " coactivators studies are beginning to reveal how these complexes are assembled bringing together " corepressors multiple functionalities that mediate: recruitment to specific genomic loci through " chromatin interaction with transcription factors; recruitment of enzymatic activities that either modify " transcriptional regulation or remodel chromatin and targeting the complexes to their chromatin substrate. These activities are regulated by post-translational modifications, alternative splicing and small signalling molecules. This review focuses on our current understanding of coregulator Journal of Molecular complexes and aims to highlight the common principles that are beginning to emerge. Endocrinology (2013) 51, T23–T36 Journal of Molecular Endocrinology Historical perspective many studies sought to identify direct interactions between nuclear receptors and components of the general Nuclear receptors are a large family of DNA-binding transcriptional machinery, based on the reasonable transcription factors that are recruited to specific DNA presumption that, like prokaryotic transcriptional activa- sequences in the genome and regulate the expression of tors, liganded nuclear receptors would directly recruit RNA genes in the proximity (!1 million base pairs) of these polymerase II or associated proteins. These interactions sites. Nuclear receptors were first cloned in 1985. Over turned out to be elusive, sparking a search for adapter the next 10 years our understanding of their molecular proteins that would make bridging interactions to the mechanisms of action grew steadily and culminated with general transcriptional machinery. Subsequently, it has the determination of the structures of the DNA- and become clear that coregulator proteins play a central ligand-binding domains (reviewed in Wurtz et al. (1996), role in the mediation of transcriptional regulation by Khorasanizadeh & Rastinejad (2001) and Bre´livet et al. nuclear receptors. (2011)). These structures revealed much about how The first nuclear receptor coregulators were discovered nuclear receptors recognise DNA and their cognate through efforts to identify proteins that interact with ligands, but did not immediately explain how their either ligand-bound or unliganded nuclear receptors recruitment to DNA changes the rate of transcription of (Halachmi et al. 1994, Baniahmad et al. 1995, Cavaille`s their target genes. In pursuit of this understanding, a great et al. 1995). This led to the identification of two classes of http://jme.endocrinology-journals.org Ñ 2013 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JME-13-0227 Printed in Great Britain This paper is one of nine papers that form part of the 25th anniversary special issue of Journal of Molecular EndocrinologyDownloaded. The Guest from Editor Bioscientifica.com for this section wasat 10/02/2021 Ronald M 10:03:33PM Evans, Investigator, Howard Hughes Medical Institute and Professor, Salk Institutevia for free access Biological Studies, La Jolla, CA, USA Thematic Review C J MILLARD and others Nuclear receptor coregulators 51:3 T24 coregulator termed as coactivator proteins, such as SRC1 ‘tethered’ to other transcription factors rather than (Onate et al. 1995), and corepressor proteins, such as directly bound to DNA themselves. Taken together, this NCoR and SMRT (Chen & Evans 1995, Ho¨rlein et al. 1995). means that the specificity of action of coregulator We now know that a very large number of proteins complexes relies upon a complicated, but specific network participate in the regulatory complexes recruited to of recruitment to various transcriptional regulators. nuclear receptors. Indeed more than 350 nuclear coregu- In the case of nuclear receptors, the presence or lators have been identified (http://www.NURSA.org). absence of a bound ligand determines which nuclear These proteins are a varied and diverse group that defy receptor coregulator complexes are recruited. Coregulator straightforward classification. However, it is important to complexes that repress transcription are generally recrui- consider some sort of definition for what is meant by ted to unliganded receptors or receptors bound to inverse coregulator proteins. agonists. In contrast, coregulator complexes that activate The broadest definition is that a coregulator is a transcription are recruited to receptors bound to agonist protein that participates in a complex that is recruited to ligands. The opposing action of these complexes has led to the genome by DNA-binding transcription factors, and the widespread use of the terms corepressor and coacti- through this recruitment, the complex regulates (up or vator complexes. However, as we suggest later, it may down) the rate of transcription of one or more genes. be better to define complexes based on their mechanism These complexes often have a universal reach throughout of action rather than the transcriptional outcome. the genome with an overarching role in the regulation of The molecular mechanisms through which nuclear transcription (Lonard & O’Malley 2012). It is important to receptors recruit coregulator complexes are now well- recognise, however, that such a broad definition results in established (reviewed in Watson et al. (2012b)). This is the a huge number of proteins being classed as coregulator result of the initial studies that identified critical sequence proteins. Indeed recent proteomic approaches have motifs in coregulator proteins that mediate ligand- identified a frighteningly large number (thousands) of dependent interactions with nuclear receptors, followed proteins as being involved in coregulator complexes by crystal structures of the ligand-binding domains of (Foulds et al. 2013). nuclear receptors in complex with these interaction In this anniversary issue, we will attempt to draw out motifs. Remarkably, most of the coactivator complexes some of the general principles that have emerged recruited to nuclear receptors do so through a conserved concerning the mechanism of action of coregulator motif with the sequence LxxLL (the so-called NR box; complexes, i.e. how they are recruited to specific genomic Heery et al. 1997). Shortly after the identification of the NR Journal of Molecular Endocrinology loci, what enzymatic activities they contain, how the box, an analogous sequence motif (LxxH/IIxxxI/L) was complexes are targeted to chromatin, how coregulator identified in corepressor proteins (Nagy et al. 1999, Hu & complexes are assembled and finally how coregulators Lazar 1999). This motif has been termed as the CoRNR themselves may be regulated. This is not a comprehensive box. Crystal structures have demonstrated that NR box review and there will be an inevitable bias towards how and CoRNR box peptides adopt an a-helical conformation structural biology has given us a better understanding of that allows them to bind in the same hydrophobic groove a small number of these complexes. on LBDs and therefore recruitment is mutually exclusive (Nolte et al. 1998, Xu et al. 2002, Wang et al. 2006, Phelan et al Recruitment to specific genomic loci . 2010). Which class of coregulator that is recruited to the LBD depends upon the ligand-dependent positioning Coregulator complexes do not themselves contain con- of the C-terminal helix (often termed helix 12) of the stitutive components that direct sequence-specific recruit- receptor (see Fig. 1). ment to particular loci in the genome. However, An important feature of the NR and CoRNR sequence recruitment to nuclear receptors and other sequence- motifs is that they are located within the regions of the specific transcription factors means that coregulator coactivator and corepressor proteins that are intrinsically activity is directed to specific genomic loci leading to disordered, i.e. do not have an intrinsically fixed structure. specific changes in gene regulation. Each coregulator The helical structure appears to be formed only on complex can be recruited to many different transcription interaction with the nuclear receptor ligand-binding factors. Similarly, each transcription factor can often domain. Strikingly, the intrinsic disorder of transcription recruit many different coregulator complexes. Further- factor interaction regions is common to many other more, the transcription factors themselves may be transcription factor interaction motifs located in these http://jme.endocrinology-journals.org Ñ 2013 Society for Endocrinology Published by Bioscientifica Ltd DOI: 10.1530/JME-13-0227 Printed in Great Britain Downloaded from Bioscientifica.com at 10/02/2021 10:03:33PM via free access Thematic Review C J MILLARD and others Nuclear receptor coregulators 51:3 T25 A B C Ac Ac CoA CoR Ac HAT HDAC Ac

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