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Mechanism of the Rpn13-induced activation of Uch37 |
Lianying Jiao1,Songying Ouyang1,Neil Shaw1,Gaojie Song2,Yingang Feng3,Fengfeng Niu1,Weicheng Qiu1,Hongtao Zhu1,Li-Wei Hung4,Xiaobing Zuo5,V. Eleonora Shtykova6,Ping Zhu1,Yu-Hui Dong7,Ruxiang Xu8,*( ),Zhi-Jie Liu1,3,*() |
1. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
2. iHuman Institute, ShanghaiTech University, Shanghai 201210, China
3. Shandong Provincial Key Laboratory of Energy Genetics, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences, Qingdao 266101, China
4. Physics Division, Los Alamos National Laboratory, Los Alamos, NM 87545, USA
5. X-ray Science Division, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, IL 60439, USA
6. Institute of Crystallography, Russian Academy of Sciences, 59 Leninsky Pr., 117333 Moscow, Russian Federation
7. Center for Multi-disciplinary Research, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China
8. Department of Nerosurgery, The Military General Hospital of Beijing PLA, Beijing 100700, China |
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Abstract 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 homodimer 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 smallangle 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. Uch37ΔHb,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. Wealso 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.
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| Keywords
Uch37-Rpn13 complex
de-ubiquitination
SAXS analysis
oligomerization
iso-peptidase
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Corresponding Author(s):
Ruxiang Xu
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Issue Date: 27 August 2014
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