CHBE Seminar: Dr. Yanxin Liu, Chemistry and Biochemistry, University of Maryland
Friday, October 14, 2022
Room 2108 Chemical and Nuclear Engineering Building
301 405 1935
A song of ice and fire: cryo-EM interrogation of the HSP90 molecular Chaperone Machinery
Heat Shock Protein 90 (Hsp90) is a ubiquitous molecular chaperone that facilitates the folding and maturation of hundreds of “client” proteins, highly enriched for signaling and regulatory processes. Despite the functional importance, how Hsp90 mediates client protein maturation and how this process is regulated by co-chaperones are largely unknown. In this presentation, I will share three stories that address these questions. First, we established the human succinate dehydrogenase B (SdhB) from respiratory complex II as the first mitochondrial Hsp90 (Trap1) client protein amenable to detailed biochemical investigation. The cryo-EM structure of the Trap1:SdhB complex elucidated the interplay between Hsp90 and partially unfolded SdhB, demonstrating a highly conserved client interaction mechanism. Second, we made an unexpected discovery that Trap1 exists in multiple tetrameric states in addition to the canonical dimeric state. With the help of SdhB, we obtained one of the tetrameric Trap1 structures at high resolution using cryo-EM. Third, we determined atomic resolution structures for cytosolic Hsp90 in complex with the ATPase-accelerating co-chaperone Aha1 in both yeast and human system. The structures revealed that Aha1 functions as a conformational and chemical activator that catalyzes the Hsp90 cycle by breaking the barriers between 6 distinct and sequentially stabilized states.