Molecular Mechanism of the Negative Regulation of Smad1/5 Protein by Carboxyl Terminus of Hsc70-interacting Protein (CHIP)

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	Molecular Mechanism of the Negative Regulation of Smad1/5 Protein by Carboxyl Terminus of Hsc70-interacting Protein (CHIP)
	Wang, Le ; Liu, Yi-Tong ; Hao, Rui ; Chen, Lei ; Chang, Zhijie ; Wang, Hong-Rui ; Wang, Zhi-Xin ; Wu, Jia-Wei ; Chen L(陈亮)
刊名	http://dx.doi.org/10.1074/jbc.M110.201814
	2011-05-06
关键词	UBIQUITIN LIGASE CHIP TGF-BETA SUPERFAMILY MEDIATED DEGRADATION SIGNALING PATHWAY OSTEOBLAST DIFFERENTIATION STRUCTURAL BASIS QUALITY-CONTROL BMP PATHWAY CHAPERONE TARGETS
英文摘要	Ministry of Science and Technology of China [2007CB914400, 2011CB910803]; National Natural Science Foundation of China [31070643]; Tsinghua University [09THZ02235]; The transforming growth factor-beta (TGF-beta) superfamily of ligands signals along two intracellular pathways, Smad2/3-mediated TGF-beta/activin pathway and Smad1/5/8-mediated bone morphogenetic protein pathway. The C terminus of Hsc70-interacting protein (CHIP) serves as an E3 ubiquitin ligase to mediate the degradation of Smad proteins and many other signaling proteins. However, the molecular mechanism for CHIP-mediated down-regulation of TGF-beta signaling remains unclear. Here we show that the extreme C-terminal sequence of Smad1 plays an indispensable role in its direct association with the tetratricopeptide repeat (TPR) domain of CHIP. Interestingly, Smad1 undergoes CHIP-mediated polyubiquitination in the absence of molecular chaperones, and phosphorylation of the C-terminal SXS motif of Smad1 enhances the interaction and ubiquitination. We also found that CHIP preferentially binds to Smad1/5 and specifically disrupts the core signaling complex of Smad1/5 and Smad4. We determined the crystal structures of CHIP-TPR in complex with the phosphorylated/pseudophosphorylated Smad1 peptides and with an Hsp70/Hsc70 C-terminal peptide. Structural analyses and subsequent biochemical studies revealed that the distinct CHIP binding affinities of Smad1/5 or Smad2/3 result from the nonconservative hydrophobic residues at R-Smad C termini. Unexpectedly, the C-terminal peptides from Smad1 and Hsp70/Hsc70 bind in the same groove of CHIP-TPR, and heat shock proteins compete with Smad1/5 for CHIP interaction and concomitantly suppress, rather than facilitate, CHIP-mediated Smad ubiquitination. Thus, we conclude that CHIP inhibits the signaling activities of Smad1/5 by recruiting Smad1/5 from the functional R-/Co-Smad complex and further promoting the ubiquitination/degradation of Smad1/5 in a chaperone-independent manner.
语种	英语
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/65540]
专题	生命科学－已发表论文
推荐引用方式 GB/T 7714	Wang, Le,Liu, Yi-Tong,Hao, Rui,et al. Molecular Mechanism of the Negative Regulation of Smad1/5 Protein by Carboxyl Terminus of Hsc70-interacting Protein (CHIP)[J]. http://dx.doi.org/10.1074/jbc.M110.201814,2011.
APA	Wang, Le.,Liu, Yi-Tong.,Hao, Rui.,Chen, Lei.,Chang, Zhijie.,...&陈亮.(2011).Molecular Mechanism of the Negative Regulation of Smad1/5 Protein by Carboxyl Terminus of Hsc70-interacting Protein (CHIP).http://dx.doi.org/10.1074/jbc.M110.201814.
MLA	Wang, Le,et al."Molecular Mechanism of the Negative Regulation of Smad1/5 Protein by Carboxyl Terminus of Hsc70-interacting Protein (CHIP)".http://dx.doi.org/10.1074/jbc.M110.201814 (2011).