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RISS 인기검색어
- 검색키워드
- 저자 : Gygi, Steven P. (검색결과 4 건)
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S5a promotes protein degradation by blocking synthesis of nondegradable forked ubiquitin chains
Kim, Hyoung Tae,Kim, Kwang Pyo,Uchiki, Tomoaki,Gygi, Steven P,Goldberg, Alfred L Wiley (John WileySons) 2009 The EMBO journal Vol.28 No.13
<P>Ubiquitin (Ub)-protein conjugates formed by purified ring-finger or U-box E3s with the E2, UbcH5, resist degradation and disassembly by 26S proteasomes. These chains contain multiple types of Ub forks in which two Ub's are linked to adjacent lysines on the proximal Ub. We tested whether cells contain factors that prevent formation of nondegradable conjugates and whether the forked chains prevent proteasomal degradation. S5a is a ubiquitin interacting motif (UIM) protein present in the cytosol and in the 26S proteasome. Addition of S5a or a GST-fusion of S5a's UIM domains to a ubiquitination reaction containing 26S proteasomes, UbcH5, an E3 (MuRF1 or CHIP), and a protein substrate, dramatically stimulated its degradation, provided S5a was present during ubiquitination. Mass spectrometry showed that S5a and GST-UIM prevented the formation of Ub forks without affecting synthesis of standard isopeptide linkages. The forked Ub chains bind poorly to 26S proteasomes unlike those synthesized with S5a present or linked to Lys63 or Lys48 chains. Thus, S5a (and presumably certain other UIM proteins) function with certain E3/E2 pairs to ensure synthesis of efficiently degraded non-forked Ub conjugates.</P>
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Chung, J.J.,Shim, S.H.,Everley, Robert A.,Gygi, Steven P.,Zhuang, X.,Clapham, David E. Cell Press ; MIT Press 2014 Cell Vol.157 No.4
Spermatozoa must leave one organism, navigate long distances, and deliver their paternal DNA into a mature egg. For successful navigation and delivery, a sperm-specific calcium channel is activated in the mammalian flagellum. The genes encoding this channel (CatSpers) appear first in ancient uniflagellates, suggesting that sperm use adaptive strategies developed long ago for single-cell navigation. Here, using genetics, super-resolution fluorescence microscopy, and phosphoproteomics, we investigate the CatSper-dependent mechanisms underlying this flagellar switch. We find that the CatSper channel is required for four linear calcium domains that organize signaling proteins along the flagella. This unique structure focuses tyrosine phosphorylation in time and space as sperm acquire the capacity to fertilize. In heterogeneous sperm populations, we find unique molecular phenotypes, but only sperm with intact CatSper domains that organize time-dependent and spatially specific protein tyrosine phosphorylation successfully migrate. These findings illuminate flagellar adaptation, signal transduction cascade organization, and fertility. PaperFlick:
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Boselli, Monica,Lee, Byung-Hoon,Robert, Jessica,Prado, Miguel A.,Min, Sang-Won,Cheng, Chialin,Silva, M. Catarina,Seong, Changhyun,Elsasser, Suzanne,Hatle, Ketki M.,Gahman, Timothy C.,Gygi, Steven P.,H American Society for Biochemistry and Molecular Bi 2017 The Journal of biological chemistry Vol.292 No.47
<P>The ubiquitin-proteasome system (UPS) is responsible for most selective protein degradation in eukaryotes and regulates numerous cellular processes, including cell cycle control and protein quality control. A component of this system, the deubiquitinating enzyme USP14, associates with the proteasome where it can rescue substrates from degradation by removal of the ubiquitin tag. We previously found that a small-molecule inhibitor of USP14, known as IU1, can increase the rate of degradation of a subset of proteasome substrates. We report here the synthesis and characterization of 87 variants of IU1, which resulted in the identification of a 10-fold more potent USP14 inhibitor that retains specificity for USP14. The capacity of this compound, IU1-47, to enhance protein degradation in cells was tested using as a reporter the microtubule-associated protein tau, which has been implicated in many neurodegenerative diseases. Using primary neuronal cultures, IU1-47 was found to accelerate the rate of degradation of wild-type tau, the pathological tau mutants P301L and P301S, and the A152T tau variant. We also report that a specific residue in tau, lysine 174, is critical for the IU1-47–mediated tau degradation by the proteasome. Finally, we show that IU1-47 stimulates autophagic flux in primary neurons. In summary, these findings provide a powerful research tool for investigating the complex biology of USP14.</P>
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Thrap3 docks on phosphoserine 273 of PPARγ and controls diabetic gene programming
Choi, Jang Hyun,Choi, Sun-Sil,Kim, Eun Sun,Jedrychowski, Mark P.,Yang, Yong Ryoul,Jang, Hyun-Jun,Suh, Pann-Ghill,Banks, Alexander S.,Gygi, Steven P.,Spiegelman, Bruce M. Cold Spring Harbor Laboratory Press 2014 Genes & development Vol.28 No.21
<P>Phosphorylation of PPARγ at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance. Choi et al. find that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPARγ when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programing mediated by the phosphorylation of PPARγ. Reduced expression of Thrap3 in fat tissue by antisense oligonucleotides improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight.</P><P>Phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance, but the underlying molecular mechanisms are unclear. We show here that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPARγ when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPARγ. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPARγ in cultured adipocytes. Importantly, reduced expression of Thrap3 in fat tissue by antisense oligonucleotides (ASOs) regulates a specific set of genes, including the key adipokines adiponectin and adipsin, and effectively improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight. These data indicate that Thrap3 plays a crucial role in controlling diabetic gene programming and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes.</P>
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