Heterotypic Assembly Mechanism Regulates CHIP E3 Ligase Activity
Heterotypic Assembly Mechanism Regulates CHIP E3 Ligase Activity
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. HIGHLIGHTSE3 ligase UFD-2 stimulates ubiquitylation activity of CHIP/CHN-1UFD-2 binding promotes dimerization of CHIP/CHN-1 U-box domains and utilization of E2 enzymesHSP70/HSP-1 by latching the U-box and TPR domains stabilizes the autoinhibitory state of CHIP/CHN-1, limiting interactions with E2s and UFD-2Assembly with UFD-2 enables CHIP/CHN-1 to regulate lipid metabolism by ubiquitylation of S-Adenosylhomocysteinase
Kr¨1ger Marcus、Das Aniruddha、Shanmugam Nilesh、Dabrowska Katarzyna、Szulc Natalia A.、Cysewski Dominik、Dadlez Michal、Hoppe Thorsten、Pokrzywa Wojciech、Nolte Hendrik、Gathungu Rose M.、Santiago Ulises、Thapa Pankaj、Banasiak Katarzyna、Nowotny Marcin、Camacho Carlos J.
Institute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne||Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital of CologneLaboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in WarsawLaboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in WarsawInstitute of Biochemistry and BiophysicsLaboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in WarsawInstitute of Biochemistry and BiophysicsInstitute of Biochemistry and BiophysicsInstitute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne||Center for Molecular Medicine (CMMC), Faculty of Medicine and University Hospital of CologneLaboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in WarsawInstitute for Genetics and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne||Max-Planck-Institute for Biology of AgeingMetabolomics Core FacilityDepartment of Computational and Systems Biology, University of PittsburghLaboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in WarsawLaboratory of Protein Metabolism, International Institute of Molecular and Cell Biology in WarsawLaboratory of Protein Structure, International Institute of Molecular and Cell Biology in WarsawDepartment of Computational and Systems Biology, University of Pittsburgh
分子生物学生物化学
C. elegansubiquitinproteostasisE3CHIPUFD-2HSP70AHCYlipids
Kr¨1ger Marcus,Das Aniruddha,Shanmugam Nilesh,Dabrowska Katarzyna,Szulc Natalia A.,Cysewski Dominik,Dadlez Michal,Hoppe Thorsten,Pokrzywa Wojciech,Nolte Hendrik,Gathungu Rose M.,Santiago Ulises,Thapa Pankaj,Banasiak Katarzyna,Nowotny Marcin,Camacho Carlos J..Heterotypic Assembly Mechanism Regulates CHIP E3 Ligase Activity[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2021.08.20.457118.点此复制
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