International Journal of Molecular Sciences Review The FKBP51 Glucocorticoid Receptor Co-Chaperone: Regulation, Function, and Implications in Health and Disease Gabriel R. Fries 1,*, Nils C. Gassen 2 and Theo Rein 2,* ID 1 Translational Psychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX 77054, USA 2 Department of Translational Science in Psychiatry, Max Planck Institute of Psychiatry, 80804 Munich, Germany; [email protected] * Correspondence: [email protected] (G.R.F.); [email protected] (T.R.); Tel.: +1-713-486-2653 (G.R.F.); +49-89-3062-2531 (T.R.) Received: 30 October 2017; Accepted: 29 November 2017; Published: 5 December 2017 Abstract: Among the chaperones and co-chaperones regulating the glucocorticoid receptor (GR), FK506 binding protein (FKBP) 51 is the most intensely investigated across different disciplines. This review provides an update on the role of the different co-chaperones of Hsp70 and Hsp90 in the regulation of GR function. The development leading to the focus on FKBP51 is outlined. Further, a survey of the vast literature on the mechanism and function of FKBP51 is provided. This includes its structure and biochemical function, its regulation on different levels—transcription, post-transcription, and post-translation—and its function in signaling pathways. The evidence portraying FKBP51 as a scaffolding protein organizing protein complexes rather than a chaperone contributing to the folding of individual proteins is collated. Finally, FKBP51’s involvement in physiology and disease is outlined, and the promising efforts in developing drugs targeting FKBP51 are discussed. Keywords: chaperone; glucocorticoid receptor; FKBP51; FKBP5; signaling pathway; drug 1. Introduction The original discovery of FK506 binding protein (FKBP) 51 was described more than 25 years ago alongside the analysis of steroid receptor complex components [1]. Accordingly, steroid receptors (SRs) and the glucocorticoid receptor (GR) in particular served as the main experimental systems for the initial investigations of FKBP51’s function and mechanism [2–5], while additional functions of FKBP51 emerged soon afterward [6]. Scientists in several laboratories characterized FKBP51 as a strong inhibitor of GR function [7–10]. Since GR is a crucial part of the stress hormone axis, also known as HPA (hypothalamus–pituitary–adrenals) axis, and since increasing evidence became available for dysregulated GR in stress-related diseases, such as depression [11], the finding of FKBP51 as an inhibitor of GR inspired a genotype association study on depression [12]. This study discovered that polymorphisms of the FKBP51-encoding gene FKBP5 were associated with stress hormone axis reactivity and response to antidepressants [12] and amplified interest in FKBP51 research worldwide (see Figure1 for a summary of the number of FKBP51-publications per year since 1990), along with the discovery of several additional functions of FKBP51 [6]. Given the importance of GR in the initial characterization of FKBP51, we will first provide an update of the contribution of chaperones and co-chaperones to GR function (Section2), with a focus on FKBP51 and a brief introduction into its structure and biochemical function (Section3). This is Int. J. Mol. Sci. 2017, 18, 2614; doi:10.3390/ijms18122614 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 2614 2 of 31 Int. J. Mol. Sci. 2017, 18, 2614 2 of 30 followedfollowed byby aa surveysurvey ofof thethe literatureliterature onon regulationregulation andand functionfunction ofof FKBP51FKBP51 (Sections(Sections4 4 and and5 )5) and and on on drugdrug developmentdevelopment effortsefforts (Section(Section6 6)) and and by by concluding concluding remarks remarks (Section (Section7). 7). FigureFigure 1.1. Number of publications on FKBP51 perper year since 1990.1990. The numbers are based onon a Pubmed searchsearch thatthat includedincluded FKBP5,FKBP5, FKBP51,FKBP51, FKBP54,FKBP54, FKBPFKBP 5,5, FKBPFKBP 51,51, andand FKBPFKBP 54.54. The initial publications describeddescribed FKBP51FKBP51 asas immunophilinimmunophilin p54.p54. ForFor 2017,2017, citationscitations werewere retrievedretrieved OctoberOctober 3030 ofof thisthis year.year. 2.2. Glucocorticoid ReceptorReceptor Co-Chaperones,Co-Chaperones, FocusFocus onon FKBP51FKBP51 TheThe glucocorticoidglucocorticoid receptor (GR) belongs to the large superfamilysuperfamily of nuclear receptors (NRs), whichwhich typicallytypically actact asas transcriptionaltranscriptional regulatorsregulators inin aa ligand-dependentligand-dependent mannermanner [[13–15].13–15]. TheyThey shareshare aa commoncommon structurestructure that that became became apparent apparent already already before before any any of theirof their genomic genomic sequence sequence was was known known [16]: an[16]: N-terminal an N-terminal activator activator domain, domain, a central a DNAcentral binding DNA domain,binding domain, and a C-terminal and a C-terminal activatordomain activator 2, whichdomain is also2, which the domain is also the of ligand domain binding of ligand [17]. binding NRs are [17]. grouped NRs intoare grouped seven subfamilies, into seven NR0-6, subfamilies, based onNR0-6, their based homology on their [18 ].homology GR, designated [18]. GR, as designated NR3C1, belongs as NR3C1, to the belongs NR3 subfamily, to the NR3 which subfamily, encompasses which allencompasses steroid hormone all steroid receptors. hormone receptors. GRGR isis functionally functionally involved involved in ain broad a broad spectrum spectrum of physiological of physiological processes, processes, including including the immune, the cardiovascular,immune, cardiovascular, reproductive, reproductive, nervous, and nervous, metabolic and system metabolic [19]. system This vast [19]. range This of vast physiological range of functionsphysiological requires functions intricate requires control intricate of its activity control [20of]. its In activity addition [20]. to molecularIn addition chaperones to molecular and co-chaperones,chaperones and which co-chaperones, predominantly which are predominantly known as regulators are known of folding as andregulators conformation of folding of GR and in theconformation cytosol, there of GR is a in vast the array cytosol, of cofactorsthere is a thatvast determine array of cofactors GR’s activity that determine as a transcription GR’s activity factor as on a thetranscription chromatin. factor These on are the not chromatin. the subject These of this are survey, not the excellent subject of reviews this survey, have been excellent published reviews [20 have–22]. been published [20–22]. 2.1. Complexity of GR Regulating Chaperones and Co-Chaperones 2.1. Complexity of GR Regulating Chaperones and Co-Chaperones The first confirmed chaperone found associated with SRs was heat shock protein (Hsp) 90 [4,23,24]. Hsp90The is afirst highly confirmed abundant chaperone protein found in eukaryotic associated cells with making SRs was up 1–2%heat shock of the protein cytosolic (Hsp) protein 90 [4,23,24]. content underHsp90 non-stressis a highly conditionsabundant protein and up in to eukaryotic 5% under ce stresslls making conditions up 1–2% [25], of now the cytosolic known as protein a key foldingcontent andunder assembly non-stress platform conditions involved and up in to numerous 5% under cellularstress conditions processes [25], [26 now–28]. known The discovery as a key folding of the core and componentsassembly platform of the GR-chaperoneinvolved in numerous heterocomplex cellula andr processes their step-wise, [26–28]. ATP-dependent The discovery assembly of the core has beencomponents described of inthe several GR-chaperone reviews [ 2heterocomplex,4,5]. Briefly, in an vitrod theirreconstitution step-wise, experimentsATP-dependent revealed assembly that fivehas chaperonesbeen described and in co-chaperones several reviews suffice [2,4,5]. to fold Briefly, GR to in a vitro conformation reconstitu withtion highexperiments affinity hormonerevealed that binding five competence:chaperones and Hsp40, co-chaperones Hsp70, hop, suffice Hsp90, to andfold p23GR [to2, 29a conformation]. The basic maturation with high stepaffinity is thought hormone to binding involve thecompetence: initial recognition Hsp40, Hsp70, of GR hop, by Hsp40,Hsp90, and which p23 leads [2,29] to. The association basic maturation with ATP-bound step is thought Hsp70 to [involve30–32]. Inthe the initial next recognition step, Hsp70-Hsp90 of GR by organizing Hsp40, which protein lead (hop)s to promotesassociation the with transfer ATP-bound of the partially Hsp70 folded[30–32]. GR In tothe the next Hsp90-based step, Hsp70-Hsp90 folding platform;organizing hop protein leaves (hop) the folding promotes complex the transfer at later of stages. the partially Hsp90 folded primarily GR actsto the on Hsp90-based the hormone folding binding platform domain; hop and leaves keeps the it folding in a hormone complex binding at later competentstages. Hsp90 state. primarily P23 is aacts cofactor on the of hormone Hsp90 that binding keeps domain Hsp90 inand the keeps ATP-bound it in a hormone state, thus binding promoting competent receptor state. binding P23 is of a Hsp90cofactor [33 of]. Hsp90 More recently,that keeps the Hsp90 coordinated in the ATP-boun action of thed state, Hsp70- thus and promoting Hsp90-based receptor cycles binding in the of folding Hsp90 and[33]. maturationMore recently, of GR the has coordinated