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The Functions of CHIP in Age Related Disease

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The Functions of CHIP in Age Related Disease Central JSM Enzymology and Protein Science Bringing Excellence in Open Access Review Article *Corresponding author Kathryn L Ball, The Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, The Functions of CHIP in Age University of Edinburgh, Western General Hospital, Crewe Road South, EH4 2XR, UK, Tel: +44 0-131-651-8500; E-mail: Related Disease Submitted: 03 August 2016 Ball KL*, Ning J, Nita E, and Dias C Accepted: 29 September 2016 Institute of Genetics and Molecular Medicine, University of Edinburgh, UK Published: 01 October 2016 Copyright Abstract © 2016 Ball et al. CHIP is a key component of the protein homeostasis or ‘Proteostasis’ network OPEN ACCESS that maintains protein structure and function as a way to ensure the integrity of the proteome in individual cells and the health of the whole organism. Proteostasis Keywords influences the biogenesis, folding, trafficking and degradation of proteins. Originally • CHIP identified as a Hsc70 associated protein and a co-chaperone CHIP has E3-ubiquitin • E3-ligase ligase activity and also displays an intrinsic chaperoning ability. It has become clear • Chaperone that CHIP is a multi-functional protein with roles in cellular processes that go beyond • Structure function its co-chaperone activity. Not surprisingly, by unravelling the functions of CHIP, we are • Neurodegeneration beginning to appreciate that loss of CHIP’s integrity can lead to the development of • Cancer several serious pathological conditions. Here we will describe the key features of CHIPs structure and functions with an emphasis on the non-canonical activities of CHIP before concentrating on the role it plays in protecting against the age associated pathologies of neurodegeneration and cancer. ABBREVIATIONS encompass the elaborate systems involved in maintaining protein structure and function as a way to ensure the integrity of the AD: Alzheimer’s Disease; CHIP: C-Terminus Of Hsc70 proteome in individual cells and the health of the whole organism. Interacting Protein; Hsc70: Heat Shock Cognate Protein 70; Hsp: Proteostasis involves a highly complex network of processes that Heat Shock Protein; RING: Really Interesting New Gene; Lys: Lysine; TPR: Tetratricopeptide Repeat; Cyp40: Cyclophilin 40; proteins. The dual function E3-ubiquitin ligase and molecular Hop: Hsp70/Hsp90 Organizing Protein; PP5: Protein Phosphatase influence the biogenesis, folding, trafficking and degradation of 5; HX-MS: Hydrogen-Deuterium Exchange Mass Spectrometry: chaperone CHIP (C-terminus of Hsc70 interacting protein) was Ppiase: Peptidylprolyl Isomerase; Bag-1: BCL2 Associated Athanogene 1; IRF-1: Interferon Regulatory Factor-1; CFTR: degradation. In addition to being a co-chaperone that targets originally identified as a link between protein folding and protein Cystic Fibrosis Transmembrane Conductance Regulator: AMP: partially-folded or unfolded client proteins for proteasomal Adenosine Monophosphate: AMPK: Adenosine Monophosphate also function independently of its Hsp-partners to control the degradation dependent on its E3-ligase activity, CHIP can Enos: Endothelial Nitric Oxide Synthase; TLR: Toll-Like Receptor; structure and function of proteins through its intrinsic chaperone IFNKinase; β: Interferon HSF1: Heat β; PKC Shock ζ: Protein Factor KinaseProtein Cζ: 1; Sirt6: α-Syn: Sirtuin-6; α-Synuclein: LKB- and/or E3-ligase activities. Besides its functions in ubiquitin- 1: Liver Kinase B1; HIF1A: Hypoxia-Inducible Factor 1-Alpha; CMA: Chaperone-Mediated Autophagy; CASA: Chaperone Assisted Selective Autophagy; MEFS: Mouse Embryonic Fibroblasts; UPS: dependent proteasome-mediated degradation, CHIP is implicated Ubiquitin Proteasome System; APP: Amyloid Precursor Protein; beginningin chaperone to appreciate dependent that autophagy loss of CHIP’s and integrityprotein cantrafficking. lead to Epidermal Growth theNot developmentsurprisingly, ofby several unravelling serious the pathological functions ofconditions. CHIP, we Here are Factor Receptor; we will introduce the general functions of CHIP with an emphasis nuclearAβ: Amyloid Factor β; Kappa-Light-Chain-EnhancerPD: Parkinson’s Disease; EGFR: Of Activated B Cells; Erbb2: Erb-B2 Receptor Tyrosine Kinase 2; NF-κB ER: Estrogen Receptor; GR: Glucocorticoid Receptor; PRMT5: age related process of neurodegeneration and tumorigenesis. Protein Arginine Methyltransferase 5; E2F1:E2F Transcription on its non-canonical activities, followed by the role of CHIP in the Factor 1; TG2: Transglutaminase 2; Bcl-2: B-Cell Lymphoma 2; Structure of chip TRAF2: TNF Receptor-Associated Factor 2; EMT: Epitheliaap1l- CHIP contains a conserved C-terminal U-box domain and Mesenchymal Transition; MMP9 :Matrix Metallopeptidase 9; Factor Beta; AP1: Activator Protein 1 MMP2 Matrix Metallopeptidase 2; TGF-β: Transforming Growth N-terminal TPR domain, which are separated by a coiled-coil INTRODUCTION region [1]. Structurally, the U-box is like a RING-finger except that it lacks metal chelating residues, playing a similar role to the RING- Protein homeostasis or ‘Proteostasis’ is the term used to finger domain in targeting the substrate and mediating ubiquitin- conjugation to it [2]. RING-finger type E3 ligases were originally Cite this article: Ball KL, Ning J, Nita E, Dias C (2016) The Functions of CHIP in Age Related Disease. JSM Enzymol Protein Sci 1(1): 1006. Ball et al. (2016) Email: Central Bringing Excellence in Open Access considered to be ‘passive’ i.e. they do not contain a catalytic site C-terminal peptide the TPR-domain becomes more stable and but instead function as scaffolds by placing the substrate and crystallography data on RING domains in complex with E2 and organized. By using a mutation at Lys30 of the TPR of CHIP, ubiquitinubiquitin-charged partners E2suggests into close a more proximity active [2].role However, in determining recent the entire TPR domain can be ‘locked’ (Figure 1). Also, changes Hsp70/90to the flexibility peptide of bindingthe TPR ordomain with theaffect replacement U-box conformation of Lys30 with[20]. anThe Ala; E3-ligase this indicates activity thatof CHIP an intra-moleculardecreased significantly allostery upon can dependentE2~Ub conformation on the E2-partner [3,4]. CHIP [7]. Whilstcan ubiquitinate Lys48-linked substrates substrates to be transmitted from the TPR domain to the U-box domain (Figure canform be either degraded Lys48-linked by the chainsproteasome [5] or andLys63-linked Lys63-linked chains chain [6], 1). Similar results were reported for Cyp40 bound to the Hsp peptides ‘XXXMEEVD’ with evidence presented that the peptide structure (PDB ID: 2C2V) for ‘nearly’ full-length murine CHIP modification results in a variety of outcomes [8,9]. The crystal on CHIP allosteric regulation suggests that cellular experiments usingcan inhibit a K30A the mutant PPIase of activityCHIP must of Cyp40be interpreted [21]. Finally, with care the [20].data can(aa25-304) catalyze was the solvedformation in 2005, of Lys63-linked and showed ubiquitin the C-terminus chains. Inof thisCHIP structure in complex a hydrophobic with Ubc13-Uev1a, ridge in Ubc13an E2 binds heterodimer into a U-box that Chip functions hydrophobic groove [10]. A subsequent structure (PDB ID: 2OXQ) Canonical activity of chip as a co-chaperone: CHIP was for the CHIP U-box from Danio rerio in complex with UbcH5a has discovered by the Patterson group [1] as a binding protein also been solved and shows a similar architecture to the murine for Hsc70; it was enriched in muscle tissue and could act as a negative regulator of Hsp70/Hsp40 chaperone function in vitro structureThe TPR-domain [11,12]. of CHIP (residues 26-131 in human) is located at the N-terminus. A TPR-domain is a 34 amino acid glucocorticoid[1]. Subsequently, receptor CHIP leading was shown to its degradationto interact withthrough Hsp90, the motif which forms a pair of anti-parallel helices that has been as well as Hsc/Hsp70, and could induce ubiquitination of the protein triage decisions impacting on the balance between folding tandem arrays of 3-16 motifs [14] and the distribution of these andubiquitin-proteasome degradation of chaperone pathway client [16]. proteins. Thus, TheCHIP role modulated of CHIP in arraysidentified can in be a broadfound rangeseparated of proteins from each [13]. otherIt is assembledor arranged in have U-Box dependent E3-ubiquitin ligase activity [22]. This led as a mediator of protein-protein interactions that facilitates the protein triage was further defined when it was demonstrated to together [15]. Generally speaking, the TPR motif can be described units generate six helices that consist of three pairs of anti- to the definition of CHIP as a co-chaperone, which together with assembly of protein complexes [15]. In CHIP, three TPR domain from a protein folding- to a protein degradation-machine [22- parallel helices. The hydrophobic surface of the TPR domain is BAG-1 [6,23], could shift the activity of the Hsc/Hsp70 chaperones responsible for the interaction with the carboxy-terminus of Hsc/ an E3-ligase that ubiquitinated unfolded or mis-folded proteins targeting24]. Thus, them the early for ubiquitin days of CHIPdependent research proteasome focused on degradation its role as of murine CHIP in complex with a Hsp90 C-terminal decapeptide only in the presence of its chaperone partners [23-25]. This wasp70 orpublished. Hsp90 [1,16]. It showed In 2005, that the the crystal TPR domain structure of (PDBCHIP ID:is similar 2C2L) canonical CHIP pathway has been covered in detail in a number of recent
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