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Components of the ubiquitin-proteasome pathway compete for surfaces on Rad23 family proteins

Goh, Amanda M. and Walters, Kylie J. and Elsasser, Suzanne and Verma, Rati and Deshaies, Raymond J. and Finley, Daniel and Howley, Peter M. (2008) Components of the ubiquitin-proteasome pathway compete for surfaces on Rad23 family proteins. BMC Biochemistry, 9 . Art. No. 4. ISSN 1471-2091. PMCID PMC2267792. https://resolver.caltech.edu/CaltechAUTHORS:GOHbmcb08

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Abstract

Background: The delivery of ubiquitinated proteins to the proteasome for degradation is a key step in the regulation of the ubiquitin-proteasome pathway, yet the mechanisms underlying this step are not understood in detail. The Rad23 family of proteins is known to bind ubiquitinated proteins through its two ubiquitin-associated (UBA) domains, and may participate in the delivery of ubiquitinated proteins to the proteasome through docking via the Rad23 ubiquitin-like (UBL) domain. Results: In this study, we investigate how the interaction between the UBL and UBA domains may modulate ubiquitin recognition and the delivery of ubiquitinated proteins to the proteasome by autoinhibition. We have explored a competitive binding model using specific mutations in the UBL domain. Disrupting the intramolecular UBL-UBA domain interactions in HHR23A indeed potentiates ubiquitin-binding. Additionally, the analogous surface on the Rad23 UBL domain overlaps with that required for interaction with both proteasomes and the ubiquitin ligase Ufd2. We have found that mutation of residues on this surface affects the ability of Rad23 to deliver ubiquitinated proteins to the proteasome. Conclusions: We conclude that the competition of ubiquitin-proteasome pathway components for surfaces on Rad23 is important for the role of the Rad23 family proteins in proteasomal targeting.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1186/1471-2091-9-4DOIArticle
http://www.biomedcentral.com/1471-2091/9/4PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267792/PubMed CentralArticle
ORCID:
AuthorORCID
Deshaies, Raymond J.0000-0002-3671-9354
Additional Information:© 2008 Goh et al., licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Submission date 24 October 2007. Acceptance date 30 January 2008. Publication date 30 January 2008. We are grateful to Shahram Misaghi for assistance with the affinity column chromatography experiments, to Eric Cooper and Michal-Ruth Schweiger for helpful discussions, and to Yang Kang for help with the model of the HHR23A UBL domain. We thank Hai Rao for the GSTUfd2-myc plasmid and Kiran Madura for the Rad23 antibody. We also thank Jennie Croyle and Melven Chok for assistance during manuscript preparation. This work was funded by grants from the National Institutes of Health CA0970004 (KJW), GM43601 (DF) and CA64888 (PMH) as well as by a scholarship from the Agency of Science, Technology and Research of Singapore (AMG). Authors’ contributions: AMG participated in the design of the study, carried out experiments and drafted the manuscript. KJW created the models of the UBL domains, participated in the design of the study and helped to revise the manuscript. SE participated in the design of the study, contributed reagents, and helped to revise the manuscript. RV performed the in vitro deubiquitination studies and helped to revise the manuscript. RJD and DF participated in the design of the study and helped to revise the manuscript. PMH participated in the design and coordination of the study and helped to revise the manuscript. All authors read and approved the final manuscript.
PubMed Central ID:PMC2267792
Record Number:CaltechAUTHORS:GOHbmcb08
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:GOHbmcb08
Alternative URL:http://dx.doi.org/10.1186/1471-2091-9-4
Usage Policy:© 2008 Goh et al., licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ID Code:9667
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:26 Feb 2008
Last Modified:03 Oct 2019 00:02

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