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Heterotypic Assembly Mechanism Regulates CHIP E3 Ligase Activity

Aniruddha Das, Pankaj Thapa, Ulises Santiago, Nilesh Shanmugam, Katarzyna Banasiak, Katarzyna Dabrowska, Hendrik Nolte, Natalia A. Szulc, Rose M. Gathungu, Dominik Cysewski, Marcus Krüger, Michal Dadlez, Marcin Nowotny, View ORCID ProfileCarlos J. Camacho, Thorsten Hoppe, View ORCID ProfileWojciech Pokrzywa
doi: https://doi.org/10.1101/2021.08.20.457118
Aniruddha Das
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Pankaj Thapa
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Ulises Santiago
8Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Nilesh Shanmugam
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Katarzyna Banasiak
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Katarzyna Dabrowska
3Institute of Biochemistry and Biophysics, PAS, Warsaw, Poland
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Hendrik Nolte
4Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
6Max-Planck-Institute for Biology of Ageing, Cologne, Germany
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Natalia A. Szulc
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Rose M. Gathungu
5Metabolomics Core Facility, EMBL, Heidelberg, Germany
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Dominik Cysewski
3Institute of Biochemistry and Biophysics, PAS, Warsaw, Poland
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Marcus Krüger
4Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
7Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital of Cologne, 50931 Cologne, Germany
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Michal Dadlez
3Institute of Biochemistry and Biophysics, PAS, Warsaw, Poland
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Marcin Nowotny
2Laboratory of Protein Structure, International Institute of Molecular and Cell Biology in Warsaw, Poland
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Carlos J. Camacho
8Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, Pennsylvania
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Thorsten Hoppe
4Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany
7Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital of Cologne, 50931 Cologne, Germany
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Wojciech Pokrzywa
1Laboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in Warsaw, Poland
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  • ORCID record for Wojciech Pokrzywa
  • For correspondence: wpokrzywa@iimcb.gov.pl
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ABSTRACT

The E3 ubiquitin ligases CHIP/CHN-1 and UFD-2 team up to accelerate ubiquitin chain formation. However, it remained largely unclear how the high processivity of this E3 set is achieved. 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. The HSP-1 chaperone outcompetes UFD-2 for CHN-1 binding and promotes the auto-inhibited CHN-1 state by acting on the conserved position of the U-box domain. The interaction with UFD-2 enables CHN-1 to efficiently ubiquitinate S-Adenosylhomocysteinase (AHCY-1), an enzyme crucial for lipid metabolism. Our results define the molecular mechanism underlying the synergistic cooperation of CHN-1 and UFD-2 in substrate ubiquitylation.

HIGHLIGHTS

  • E3 ligase UFD-2 stimulates ubiquitylation activity of CHIP/CHN-1

  • UFD-2 binding promotes dimerization of CHIP/CHN-1 U-box domains and utilization of E2 enzymes

  • HSP70/HSP-1 by latching the U-box and TPR domains stabilizes the autoinhibitory state of CHIP/CHN-1, limiting interactions with E2s and UFD-2

  • Assembly with UFD-2 enables CHIP/CHN-1 to regulate lipid metabolism by ubiquitylation of S-Adenosylhomocysteinase

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted August 20, 2021.
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Heterotypic Assembly Mechanism Regulates CHIP E3 Ligase Activity
Aniruddha Das, Pankaj Thapa, Ulises Santiago, Nilesh Shanmugam, Katarzyna Banasiak, Katarzyna Dabrowska, Hendrik Nolte, Natalia A. Szulc, Rose M. Gathungu, Dominik Cysewski, Marcus Krüger, Michal Dadlez, Marcin Nowotny, Carlos J. Camacho, Thorsten Hoppe, Wojciech Pokrzywa
bioRxiv 2021.08.20.457118; doi: https://doi.org/10.1101/2021.08.20.457118
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Heterotypic Assembly Mechanism Regulates CHIP E3 Ligase Activity
Aniruddha Das, Pankaj Thapa, Ulises Santiago, Nilesh Shanmugam, Katarzyna Banasiak, Katarzyna Dabrowska, Hendrik Nolte, Natalia A. Szulc, Rose M. Gathungu, Dominik Cysewski, Marcus Krüger, Michal Dadlez, Marcin Nowotny, Carlos J. Camacho, Thorsten Hoppe, Wojciech Pokrzywa
bioRxiv 2021.08.20.457118; doi: https://doi.org/10.1101/2021.08.20.457118

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