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Mechanism of the Rpn13-induced activation of Uch37
Jiao, LY; Ouyang, SY; Shaw, N; Song, GJ; Feng, YG; Niu, FF; Qiu, WC; Zhu, HT; Hung, LW; Zuo, XB; Shtykova, VE; Zhu, P; Dong, YH; Xu, RX; Liu, ZJ;董宇辉
2014
发表期刊PROTEIN & CELL
卷号5期号:8页码:616-630
摘要Uch37 is a de-ubiquitinating enzyme that is activated by Rpn13 and involved in the proteasomal degradation of proteins. The full-length Uch37 was shown to exhibit low iso-peptidase activity and is thought to be auto-inhibited. Structural comparisons revealed that within a homo-dimer of Uch37, each of the catalytic domains was blocking the other's ubiquitin (Ub)-binding site. This blockage likely prevented Ub from entering the active site of Uch37 and might form the basis of auto-inhibition. To understand the mode of auto-inhibition clearly and shed light on the activation mechanism of Uch37 by Rpn13, we investigated the Uch37-Rpn13 complex using a combination of mutagenesis, biochemical, NMR, and small-angle X-ray scattering (SAXS) techniques. Our results also proved that Uch37 oligomerized in solution and had very low activity against the fluorogenic substrate ubiquitin-7-amino-4-methylcoumarin (Ub-AMC) of de-ubiquitinating enzymes. Uch37 Delta(Hb,Hc,KEKE), a truncation removal of the C-terminal extension region (residues 256-329) converted oligomeric Uch37 into a monomeric form that exhibited iso-peptidase activity comparable to that of a truncation-containing the Uch37 catalytic domain only. We also demonstrated that Rpn13C (Rpn13 residues 270-407) could disrupt the oligomerization of Uch37 by sequestering Uch37 and forming a Uch37-Rpn13 complex. Uch37 was activated in such a complex, exhibiting 12-fold-higher activity than Uch37 alone. Time-resolved SAXS (TR-SAXS) and FRET experiments supported the proposed mode of auto-inhibition and the activation mechanism of Uch37 by Rpn13. Rpn13 activated Uch37 by forming a 1:1 stoichiometric complex in which the active site of Uch37 was accessible to Ub.
关键词Uch37-Rpn13 complex de-ubiquitination SAXS analysis oligomerization iso-peptidase
学科领域Cell Biology
DOI10.1007/s13238-014-0046-z
收录类别SCI
WOS记录号WOS:000340566500005
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被引频次:15[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.ihep.ac.cn/handle/311005/225316
专题多学科研究中心
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GB/T 7714
Jiao, LY,Ouyang, SY,Shaw, N,et al. Mechanism of the Rpn13-induced activation of Uch37[J]. PROTEIN & CELL,2014,5(8):616-630.
APA Jiao, LY.,Ouyang, SY.,Shaw, N.,Song, GJ.,Feng, YG.,...&Liu, ZJ;董宇辉.(2014).Mechanism of the Rpn13-induced activation of Uch37.PROTEIN & CELL,5(8),616-630.
MLA Jiao, LY,et al."Mechanism of the Rpn13-induced activation of Uch37".PROTEIN & CELL 5.8(2014):616-630.
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