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Ubiquitin modification of proteomic analysis and HDAC5 Sumo modification mechanism

Author: TanFengWei
Tutor: QiangBoQin;LuoZuo;YuanJianGang;PengXiaoZhong
School: Peking Union Medical College , China
Course: Biochemistry and Molecular Biology
Keywords: Graduate thesis Proteomics Medical Proteasome Concord Lysine Affinity chromatography Immunoprecipitation Histone Identified by mass spectrometry
CLC: Q3
Type: PhD thesis
Year: 2007
Downloads: 229
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Abstract


Ubiquitin is a highly conserved 76-amino acid polypeptide expressed in all eukaryotes but absent in bacteria and archaea. Polyubiquitin through Lys48 linkage targets modified proteins for ATP-dependent degradation by the 26S proteasome. Ubiquitination plays an essential role in cellular functions such as cell cycle progressing, cellular proliferation and differentiation, apoptosis, etc. UBLs (ubiquitin-like modifers) that share similarities with ubiquitin as a post- translational protein modifier have been identified in eukaryotic cells. The most well studied member of this ubiquitin-like family is Sumo (Small Ubiquitin-like modifier). With an ubiquitin-like 3D structure, Sumo is conjugated to proteins via a similar mechanism as ubiquitin. Unlike ubiquitination, which usually targets proteins to degaradation, sumolation mediates a number of cellular processes by regulate the behaviors of substrate proteins such as subcellular localization, enzymatic activity, protein-protein interaction. Here, we studied the ubiquitination in liver cells by proteomic approach and the sumolation of HDAC5 respectively.We purified and identified the ubiquitinated proteins by proteomics-based approaches. The S5a subunit of 26S proteasome was originally identified as a protein capable of binding poly ubiquitin chains through Lys48 linkage. 81 putative polyubiquitinated proteins in normal liver cells (Chang’ liver cell) were identified in this study using S5a-affinity chromatography coupled LC/LC-MS/MS analysis. Moreover, 19 putative ubiquitination sites were identified by mass spectrometry.Moreover, we show that HDAC5 is sumolated in vivo and this modification is regulated by PIASs. By deacetylating histone and modifying chramotin structure, HDACs (Histone Deacetylase) play essential roles in regulating gene expression. Previous research showed that HDAC4 is modified by sumo, we found that HDAC5 is a new substrate of sumo by in vivo sumoylation assays in this report. PIASs (Protein Inhibitors of Activated STAT Protein), which contain a conserved SP-RING domain, are considered as the common E3 ligase in sumolation pathway. After confirming the interaction between PIASs and HDAC5 by co-immunoprecipitation, we found that PIAS1 enhances the Sumo1-modification of HDAC5, while PIASy enhances the Sumo2-modification of HDAC5 specifically. Our data also showed that K606 on HDAC5, which matches a consensus sumoylation motif, is a specifical Sumo2/3 modification site. Bioinforrnatic analysis leads us to assume that the sumolation on conserved region (about the 600 amino acid from the N-terminus) is a common characteristic of ClassⅡa HDACs.

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