期刊
EMBO JOURNAL
卷 41, 期 15, 页码 -出版社
WILEY
DOI: 10.15252/embj.2021109566
关键词
C; elegans; CHIP; STUB1; CHN-1; metabolism; ubiquitin ligase; UFD-2
资金
- NIH National Center for Research Resources [P40 OD010440, SCR_021630]
- Foundation for Polish Science
- European Union under the European Regional Development Fund [POIR.04.04.00-00-5EAB/18-00]
- National Science Center, Poland [2016/23/B/NZ3/00753, 2021/41/N/NZ1/03086]
- International Institute of Molecular and Cell Biology in Warsaw under an internal collaborative project fund
- National Multidisciplinary Laboratory of Functional Nanomaterials [POIGT.02.02.00-00-025/09-00]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy -EXC [ZUK81/1]
- European Research Council [ZUK81/1, ERC-CoG-616499]
- German Research Foundation (DFG) [EXC 2030-390661388]
- National Institute of Health [R01-GM097082]
The study revealed that UFD-2 binding enhances cooperation between CHN-1 and ubiquitin-conjugating E2 enzymes, while HSP70/HSP-1 chaperone protein restricts this cooperation, leading CHN-1 to an autoinhibited state. This finding elucidates the molecular mechanism underlying the synergistic cooperation of CHN-1 and UFD-2 in substrate ubiquitylation.
CHIP (C-terminus of Hsc70-interacting protein) and its worm ortholog CHN-1 are E3 ubiquitin ligases that link the chaperone system with the ubiquitin-proteasome system (UPS). CHN-1 can cooperate with UFD-2, another E3 ligase, to accelerate ubiquitin chain formation; however, the basis for the high processivity of this E3s set has remained obscure. Here, we studied the molecular mechanism and function of the CHN-1-UFD-2 complex in Caenorhabditis elegans. Our data show that UFD-2 binding promotes the cooperation between CHN-1 and ubiquitin-conjugating E2 enzymes by stabilizing the CHN-1 U-box dimer. However, HSP70/HSP-1 chaperone outcompetes UFD-2 for CHN-1 binding, thereby promoting a shift to the autoinhibited CHN-1 state by acting on a conserved residue in its U-box domain. The interaction with UFD-2 enables CHN-1 to efficiently ubiquitylate and regulate S-adenosylhomocysteinase (AHCY-1), a key enzyme in the S-adenosylmethionine (SAM) regeneration cycle, which is essential for SAM-dependent methylation. Our results define the molecular mechanism underlying the synergistic cooperation of CHN-1 and UFD-2 in substrate ubiquitylation.
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