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C-terminal UBA domains protect ubiquitin receptors by preventing initiation of protein degradation

By Christian Heinen, Klàra Ács, Deborah Hoogstraten and Nico P. Dantuma

Abstract

The ubiquitin receptors Rad23 and Dsk2 deliver polyubiquitylated substrates to the proteasome for destruction. The C-terminal ubiquitin-associated (UBA) domain of Rad23 functions as a cis-acting stabilization signal that protects this protein from proteasomal degradation. Here, we provide evidence that the C-terminal UBA domains guard ubiquitin receptors from destruction by preventing initiation of degradation at the proteasome. We show that introduction of unstructured polypeptides that are sufficiently long to function as initiation sites for degradation abrogates the protective effect of UBA domains. Vice versa, degradation of substrates that contain an unstructured extension can be attenuated by the introduction of C-terminal UBA domains. Our study gains insight into the molecular mechanism responsible for the protective effect of UBA domains and explains how ubiquitin receptors can shuttle substrates to the proteasome without themselves becoming subject to proteasomal degradation

Topics: Article
Publisher: Nature Publishing Group
OAI identifier: oai:pubmedcentral.nih.gov:3105319
Provided by: PubMed Central

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Citations

  1. (2000). 3-Methyladenine-DNA glycosylase (MPG protein) interacts with human RAD23 proteins.
  2. (2009). A conserved unfoldase activity for the p97 AAA-ATPase in proteasomal degradation.
  3. (2000). A gated channel into the proteasome core particle.
  4. (2005). A series of ubiquitin binding factors connects CDC48/p97 to substrate multiubiquitylation and proteasomal targeting.
  5. (1998). A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3.
  6. (2006). A ubiquitin-interacting motif protects polyubiquitinated Met4 from degradation by the 26S proteasome.
  7. (2004). An unstructured initiation site is required for efficient proteasome-mediated degradation.
  8. (2000). Biochemical and structural analysis of the interaction between the UBA(2) domain of the DNA repair protein HHR23A and HIV-1 Vpr.
  9. (2005). Budding yeast Dsk2 protein forms a homodimer via its C-terminal UBA domain.
  10. (2005). Delivery of ubiquitinated substrates to proteinunfolding machines.
  11. (2005). Diverse polyubiquitin interaction properties of ubiquitin-associated domains.
  12. (2002). Identification of ubiquitin-like protein-binding subunits of the 26S proteasome.
  13. (2003). Inhibition of ubiquitin/proteasome-dependent proteolysis in Saccharomyces cerevisiae by a Gly-Ala repeat.
  14. (2009). Insights into the molecular architecture of the 26S proteasome.
  15. (2009). Minimal length requirement for proteasomal degradation of ubiquitin-dependent substrates.
  16. (2010). Monoubiquitination of RPN10 regulates substrate recruitment to the proteasome.
  17. (2004). Multiubiquitin chain receptors define a layer of substrate selectivity in the ubiquitin-proteasome system.
  18. (2010). Mutant p62/SQSTM1 UBA domains linked to Paget’s disease of bone differ in their abilities to function as stabilization signals.
  19. (1979). Physiologically relevant and portable tandem ubiquitinbinding domain stabilizes polyubiquitylated proteins.
  20. (2007). Proteasome inhibition in wild-type yeast Saccharomyces cerevisiae cells.
  21. (2007). Proteasome substrate degradation requires association plus extended peptide.
  22. (2002). Proteasome subunit Rpn1 binds ubiquitin-like protein domains.
  23. (1999). Proteasomes and other selfcompartmentalizing proteases in prokaryotes.
  24. (2001). Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome.
  25. (2004). Proteolysis-independent regulation of the transcription factor Met4 by a single Lys 48-linked ubiquitin chain.
  26. (1998). Rad23 links DNA repair to the ubiquitin/proteasome pathway.
  27. (2001). Rad23 provides a link between the Png1 deglycosylating enzyme and the 26 S proteasome in yeast.
  28. (2009). Recognition and processing of ubiquitin-protein conjugates by the proteasome.
  29. (2000). Recognition of the polyubiquitin proteolytic signal.
  30. (2000). Regulation of transcription by ubiquitination without proteolysis: Cdc34/SCF(Met30)-mediated inactivation of the transcription factor Met4. Cell 102,
  31. (2000). Short-lived green fluorescent proteins for quantifying ubiquitin/proteasome-dependent proteolysis in living cells.
  32. (2002). Solution structures of UBA domains reveal a conserved hydrophobic surface for protein-protein interactions.
  33. (2005). Structural determinants for selective recognition of a Lys48-linked polyubiquitin chain by a UBA domain.
  34. (2006). Structures of the Dsk2 UBL and UBA domains and their complex.
  35. (2009). Substrate selection by the proteasome during degradation of protein complexes.
  36. (2008). The central unit within the 19S regulatory particle of the proteasome.
  37. (2000). The DNA repair protein rad23 is a negative regulator of multi-ubiquitin chain assembly.
  38. (1996). The multiubiquitin-chain-binding protein Mcb1 is a component of the 26S proteasome in Saccharomyces cerevisiae and plays a nonessential, substrate-specific role in protein turnover.
  39. (2005). The UBA2 domain functions as an intrinsic stabilization signal that protects Rad23 from proteasomal degradation.
  40. (1998). The ubiquitin system.
  41. (2006). Ubiquitin chains are remodeled at the proteasome by opposing ubiquitin ligase and deubiquitinating activities.
  42. (2008). Ubiquitin recognition by the ubiquitin-associated domain of p62 involves a novel conformational switch.
  43. (2001). Ubiquitin-associated (UBA) domains in Rad23 bind ubiquitin and promote inhibition of multi-ubiquitin chain assembly.
  44. (1996). Yeast ubiquitin-like genes are involved in duplication of the microtubule organizing center.