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Design of linked-domain protein inhibitors of UBE2D as tools to study cellular ubiquitination.
Bukhari, Zara; Gu, Li; Nederstigt, Anneroos E; Cope, Logan J; Bolhuis, Derek L; Harvey, Kim; Allen, Tristan; Hill, Spencer; Yang, Yujie; Lawson, Guy; Lu, Cai; Tran, Tommy; Pineda, Leah; Low, Leanne; Chiang, Andrew; Song, Jason; Fong, Michelle V; Rangel, Vanessa M; Chan, William K; Kleiger, Gary; Goldfarb, Dennis; Vierra, Craig A; Brown, Nicholas G; Harrison, Joseph S.
Afiliação
  • Bukhari Z; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Gu L; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Nederstigt AE; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Cope LJ; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Bolhuis DL; Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
  • Harvey K; Department of Biochemistry and Biophysics, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
  • Allen T; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Hill S; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Yang Y; Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA.
  • Lawson G; Department of Pharmaceutics & Medicinal Chemistry, Thomas J. Long School of Pharmacy, University of the Pacific, Stockton, CA 95211, USA.
  • Lu C; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Tran T; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Pineda L; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Low L; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Chiang A; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Song J; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Fong MV; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Rangel VM; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Chan WK; The University of the Pacific, Department of Chemistry, Stockton, CA, 95210, USA.
  • Kleiger G; Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA.
  • Goldfarb D; Department of Chemistry and Biochemistry, University of Nevada, Las Vegas, Las Vegas, NV, USA.
  • Vierra CA; Department of Cell Biology and Physiology, Institute for Informatics, Washington University, St. Louis, MO, USA.
  • Brown NG; Biological Sciences Department, University of the Pacific, Stockton, CA 95211, USA.
  • Harrison JS; Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC, USA.
bioRxiv ; 2024 Sep 02.
Article em En | MEDLINE | ID: mdl-39282319
ABSTRACT
Ubiquitin (Ub) is a post-translational modification that largely controls proteostasis through mechanisms spanning transcription, translation, and notably, protein degradation. Ub conjugation occurs through a hierarchical cascade of three enzyme classes (E1, E2, and E3s) involving >1000 proteins that regulate the ubiquitination of proteins. The E2 Ub-conjugating enzymes are the midpoint, yet their cellular roles remain under-characterized, partly due to a lack of inhibitors. For example, the cellular roles of the promiscuous E2 UBE2D/UBCH5 are not well described. Here, we develop a highly selective, multivalent, engineered protein inhibitor for the UBE2D family that simultaneously targets the RING- and backside-binding sites. In HeLa cells, these inhibitors phenocopy knockdown of UBE2D by reducing the IC50 to cisplatin and whole-cell proteomics reveal an increased abundance of ~20% of the identified proteins, consistent with reduced Ub degradation and proteotoxic stress. These precision tools will enable new studies probing UBE2D's central role in proteome management.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: BioRxiv Ano de publicação: 2024 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos