Speaker: Dingyin Tao, National Center for Advancing Translational Sciences, NIH
Topic: From Mass Spectrometry-Based Proteomics to Patient Care
Date: December 11, 2023
Time: 6:15 pm Dinner, 7:15 pm Presentation
Location: Shimadzu Scientific Instrument, Inc. Training Center 7100 Riverwood Drive, Columbia, MD 21046 (Directions)
Dinner: Please RSVP to Jonathan Ferguson (firstname.lastname@example.org) by Friday, December 8 if you will be attending the dinner.
Abstract: Mass spectrometry-based proteomics plays a vital role in various stages of translational science, e.g. biomarker discovery and drug target identification. I will discuss these two separate cases: the first part focuses on the discovery of 35 parasite markers from which we selected a single candidate for use in a point-of-need (PON) rapid diagnostic test. We performed a cross-sectional, multi-omics study of saliva from 364 children with subclinical infection in Cameroon and Zambia, and produced a prototype saliva-based PON lateral flow immunoassay test for P. falciparum gametocyte carriers. This assay is being commercialized by a company founded in South Africa. The second part focuses on a new drug target for an old drug, Auranofin. UBA1 is the primary E1 ubiquitin-activating enzyme responsible for generation of activated ubiquitin required for ubiquitination, a process that regulates stability and function of numerous proteins. Abnormal UBA1 activity or ubiquitination causes or drives many human diseases, such as cancer, major neurodegenerative diseases, Angelman syndrome, VEXAS syndrome, and spinal muscular atrophy, as well as aging, highlighting the importance of the discovery of small molecule modulators of UBA1 activity for research and therapeutic purposes. Auranofin, a drug approved for the treatment of rheumatoid arthritis, was found in our high-throughput compound screen assay. Furthermore, HPLC-MS/MS was used to identify UBA1 as the new drug target of Auranofin. Through proteomics analysis, it was confirmed that auranofin binds to UBA1’s ubiquitin fold domain and conjugates to the Cys 1039 residue. This binding enhances interactions of UBA1 with at least 20 different E2 ubiquitin-conjugating enzymes, facilitating ubiquitin charging to E2 and increasing the activities of seven representative E3s in vitro. Auranofin promotes ubiquitination and degradation of misfolded ER proteins during ER-associated degradation in cells at low nanomolar concentrations. It also facilitates outer mitochondrial membrane-associated degradation. These findings suggest auranofin can serve as a much-needed tool for UBA1 research and therapeutic exploration.
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