Das, Aniruddha ORCID: 0000-0002-7704-3573, Thapa, Pankaj ORCID: 0000-0001-5536-1768, Santiago, Ulises, Shanmugam, Nilesh, Banasiak, Katarzyna ORCID: 0000-0002-1027-9426, Dabrowska, Katarzyna ORCID: 0000-0001-7833-0374, Nolte, Hendrik, Szulc, Natalia A., Gathungu, Rose M., Cysewski, Dominik ORCID: 0000-0001-6206-0672, Krueger, Marcus, Dadlez, Michal ORCID: 0000-0001-8811-5176, Nowotny, Marcin, Camacho, Carlos J., Hoppe, Thorsten and Pokrzywa, Wojciech (2022). A heterotypic assembly mechanism regulates CHIP E3 ligase activity. Embo J., 41 (15). HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Das, AniruddhaUNSPECIFIEDorcid.org/0000-0002-7704-3573UNSPECIFIED
Thapa, PankajUNSPECIFIEDorcid.org/0000-0001-5536-1768UNSPECIFIED
Santiago, UlisesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shanmugam, NileshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Banasiak, KatarzynaUNSPECIFIEDorcid.org/0000-0002-1027-9426UNSPECIFIED
Dabrowska, KatarzynaUNSPECIFIEDorcid.org/0000-0001-7833-0374UNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Szulc, Natalia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gathungu, Rose M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cysewski, DominikUNSPECIFIEDorcid.org/0000-0001-6206-0672UNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dadlez, MichalUNSPECIFIEDorcid.org/0000-0001-8811-5176UNSPECIFIED
Nowotny, MarcinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Camacho, Carlos J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoppe, ThorstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pokrzywa, WojciechUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-688476
DOI: 10.15252/embj.2021109566
Journal or Publication Title: Embo J.
Volume: 41
Number: 15
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
MOLECULAR-DYNAMICS SIMULATIONS; UBIQUITIN-LIGASE; STRUCTURAL INSIGHTS; CHAPERONE UNC-45; PROTEIN; CHAIN; IDENTIFICATION; COMPLEX; UBE2W; HSP70Multiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68847

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