CHIP Is a U-box-dependent E3 Ubiquitin Ligase

Jiang, Jihong; Ballinger, Carol A.; Wu, Yaxu; Dai, Qian; Cyr, Douglas M.; Höhfeld, Jörg; Patterson, Cam

doi:10.1074/jbc.m101968200

Cited by 528 publications

(235 citation statements)

References 37 publications

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“…CHIP also displays E3 ubiquitin ligase activity mediated by its U-box domain. CHIP can interact with BAG-1, and both proteins may be involved in the ubiquitination and proteasome-mediated degradation of proteins (73), including several membrane-bound receptors as well as Hsc 70, in a chaperone-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Rat Brain Postsynaptic Density

Hornshaw

Schors

et al. 2004

Journal of Biological Chemistry

235

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The postsynaptic density contains multiple protein complexes that together relay the presynaptic neurotransmitter input to the activation of the postsynaptic neuron. In the present study we took two independent proteome approaches for the characterization of the protein complement of the postsynaptic density, namely 1) two-dimensional gel electrophoresis separation of proteins in conjunction with mass spectrometry to identify the tryptic peptides of the protein spots and 2) isolation of the trypsin-digested sample that was labeled with isotope-coded affinity tag, followed by liquid chromatography-tandem mass spectrometry for the partial separation and identification of the peptides, respectively. Functional grouping of the identified proteins indicates that the postsynaptic density is a structurally and functionally complex organelle that may be involved in a broad range of synaptic activities. These proteins include the receptors and ion channels for glutamate neurotransmission, proteins for maintenance and modulation of synaptic architecture, sorting and trafficking of membrane proteins, generation of anaerobic energy, scaffolding and signaling, local protein synthesis, and correct protein folding and breakdown of synaptic proteins. Together, these results imply that the postsynaptic density may have the ability to function (semi-) autonomously and may direct various cellular functions in order to integrate synaptic physiology.The majority of excitatory neurotransmission in the brain occurs via glutamatergic synapses. In the presynaptic element of the synapse, specialized secretion machinery determines the activity-dependent membrane fusion of glutamate-containing vesicles and the release of transmitter into the synaptic cleft. In the postsynaptic element, glutamate receptors and downstream signal transduction are organized by the protein assembly of the postsynaptic density (PSD). 1 Both the presynaptic release machinery and the PSD are electron-dense assemblies (1, 2), in which proteins are thought to be organized into distinct functional complexes (3-5) that may be dynamically regulated by neuronal activity (6 -8). The modulation of this molecular architecture of the synapse is at the basis of synaptic plasticity (6 -8), and aberrations thereof may underlie neuronal disorders.In view of the importance of the PSD in glutamatergic neurotransmission and its involvement in neuroplasticity, considerable efforts have been made to identify its protein constituents as a prelude to understand the molecular basis of PSD functioning. In the past several years, yeast two-hybrid technology has been extensively used to characterize proteins that interact with the glutamate receptors and may constitute core elements of the PSD involved in the regulation of receptor trafficking and signaling (reviewed in Refs. 9 -11). Based largely on these studies a protein-protein interaction map of the PSD has emerged. In brief, the model posits that the postsynaptic receptor complexes are localized by scaffolding proteins such as the s...

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Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of Rat Brain Postsynaptic Density

Hornshaw

Schors

et al. 2004

Journal of Biological Chemistry

235

View full text Add to dashboard Cite

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“…In this case, none of the positive clones that grew on synthetic medium lacking Leu, Trp, and His coded for CHIP. 4 CHIP is a U-box-containing ubiquitin-protein isopeptide ligase (E3) (23)(24)(25)(26) that interacts with heat shock proteins Hsp70 and Hsp90 through its NH 2 -terminal TPR domain (Fig. 3A) and has been reported to cause ubiquitylation of AR (13).…”

Section: Ar Nh 2 -Terminal Conserved Motif Interaction With Chip-mentioning

confidence: 99%

An Androgen Receptor NH2-terminal Conserved Motif Interacts with the COOH Terminus of the Hsp70-interacting Protein (CHIP)

He¹,

Bai²,

Hnat³

et al. 2004

Journal of Biological Chemistry

Self Cite

122

113

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The NH 2 -terminal sequence of steroid receptors is highly variable between different receptors and in the same receptor from different species. In this study, a primary sequence homology comparison identified a 14-amino acid NH 2 -terminal motif of the human androgen receptor (AR) that is common to AR from all species reported, including the lower vertebrates. The evolutionarily conserved motif is unique to AR, with the exception of a partial sequence in the glucocorticoid receptor of higher species. The presence of the conserved motif in AR and the glucocorticoid receptor and its absence in other steroid receptors suggests convergent evolution. The function of the AR NH 2 -terminal conserved motif was suggested from a yeast two-hybrid screen that identified the COOH terminus of the Hsp70-interacting protein (CHIP) as a binding partner. We found that CHIP functions as a negative regulator of AR transcriptional activity by promoting AR degradation. In support of this, two mutations in the AR NH 2 -terminal conserved motif previously identified in the transgenic adenocarcinoma of mouse prostate model reduced the interaction between CHIP and AR. Our results suggest that the AR NH 2 -terminal domain contains an evolutionarily conserved motif that functions to limit AR transcriptional activity. Moreover, we demonstrate that the combination of comparative sequence alignment and yeast two-hybrid screening using short conserved peptides as bait provides an effective strategy to probe the structure-function relationships of steroid receptor NH 2 -terminal domains and other intrinsically unstructured transcriptional regulatory proteins.Steroid receptors depend on multiple domains for their function as ligand-dependent transcriptional activators. The DNAand ligand-binding domains have been studied extensively and have a high degree of structural and functional conservation. In contrast, the largely unstructured NH 2 -terminal domains (1-3) are highly variable in size and sequence, and the molecular mechanisms that contribute to transactivation are not well understood. The size of the NH 2 -terminal region of steroid receptors increases with evolutionary expansion (4, 5), from estrogen receptor-␣ (185 amino acid residues) to the glucocorticoid receptor (GR 1 ; 420 residues), androgen receptor (AR; 558 residues), progesterone receptor (B form; 566 residues), and mineralocorticoid receptor (602 residues). In contrast, transcription factors such as p53, NF-B, and VP16 typically have transcriptional activation domains of Ͻ100 residues.

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“…In studies so far, the E3 ubiquitin ligase uses protein-protein interaction domains outside the catalytic domain to bind substrate ( Figure 1). To date, there are two major structural classes of E3 ubiquitin ligases, although newer studies suggest additional domains may possess E3 activity (Hatakeyama et al, 2001;Jiang et al, 2001;Lu et al, 2002;Patterson, 2002). Of the two major classes, the HECT domain proteins are a modest sized family of proteins with no currently known connections to centrosome biology.…”

Section: The Biochemistry Of Ubiquitin Ligasesmentioning

confidence: 99%