Hundreds of ubiquitylation pathways conjugate complex patterns of ubiquitins on numerous protein substrates to alter their properties, such as stability, localization, activity and interaction partners. Due to the complexity and experimental challenges, we still do not understand the rules by which the proteasome recognizes this ubiquitin code and commits the destined substrate into an irreversible degradation process.
In previous studies, we introduced chemical methods for generating substrates with defined ubiquitin configurations, and developed single-molecule kinetics approaches to illuminate the transient reaction steps and reaction intermediates. We also developed high-throughput methods to identify the ubiquitin configurations on physiological substrates. Powered by these novel technologies, we aim to understand how the ubiquitylation patterns on substrates, through interacting with the multitude of ubiquitin receptors on the proteasome, control the key steps in proteasomal degradation to regulate protein stability.
Related publications:
- Ying Lu, Byung-hoon Lee, Randall King, Daniel Finley and Marc W. Kirschner (2015). Substrate Degradation by the Proteasome: A Single-Molecule Kinetic Analysis. Science, 348:1250834.
- Ying Lu, Weiping Wang, and Marc W. Kirschner (2015). Specificity of the Anaphase-Promoting Complex: A Single-Molecule Study. Science 348:1248737.
- Byung-Hoon Lee, Ying Lu, Miguel A. Prado, Yuan Shi, Shuangwu Sun, Suzanne Elsasser, Marc W. Kirschner, Steven P. Gygi, Randall W. King, and Daniel Finley (2016). USP14 Deubiquitinates Proteasome-bound Substrates that are Ubiquitinated at Multiple Sites. Nature 532:398-401.
- Nicholas G. Brown, Ryan VanderLinden, Edmond R. Watson, Florian Weissmann, Alban Ordureau, Kuen-Phon Wu, Wei Zhang, Shanshan Yu, Joseph S. Harrison, Renping Q. Coudevylle, Iain F. Davidson, Ying Lu, Prakash Dube, Michael R. Brunner, Christy R. R. Grace, Darcie J. Miller, Marc A. Jarvis, Masaya Yamaguchi, Peter Y. Mercredi, Sachdev S. Sidhu, Brian Kuhlman, Marc W. Kirschner, J. Wade Harper, Jan-Michael Peters, Holger Stark, Brenda A. Schulman (2016). Dual RING E3 Architectures for Substrate Polyubiquitination Visualized for Anaphase Promoting Complex/Cyclosome. Cell 165(6);1440-53.
- Jason Hon, and Ying Lu* (2018). Single-molecule methods for measuring ubiquitination and protein stability. Methods in Enzymology 619: 225-247. *corresponding author *review article