BBE Division Seminar - Andy Martin

"Molecular machines for protein destruction:
Substrate processing by AAA+ ATPases of the Ubiquitin-Proteasome System"

The ubiquitin-proteasome system is the major degradation pathway for protein quality control and the regulation of vital processes in eukaryotic cells, and therefore also plays important roles in the development of various human diseases. Elucidating the principles for 26S proteasome biogenesis, substrate recruitment, and mechanical processing is thus critical for advancing our understanding of the proteasome's numerous cellular functions.

Our biochemical, single-molecule, and cryo-EM structural studies of the 26S proteasome provide new mechanistic insights into the complex assembly process of the proteasomal ATPase motor, the recognition of protein substrates in ubiquitin-dependent and -independent manners, and their ATP-dependent degradation. Visualizing the hetero-hexameric ATPase motor in different conformations and nucleotide states, and monitoring its movements by single-molecule FRET give a glimpse into the mechanochemical coupling that drives substrate translocation by asymmetric firing of the six cylinders.

Furthermore, our studies of p97, an ATPase acting upstream of the proteasome, elucidate how this motor collaborates with several UBX-domain containing cofactors to efficiently engage and unfold ubiquitinated proteins for subsequent proteasomal degradation.

These studies not only advance our understanding of the basic principles that underlie substrate turnover by the ubiquitin-proteasome system, but may also help in developing new therapeutic strategies, for instance to target unwanted or aberrant proteins, and thus treat cancers, neurodegenerative disorders, and other diseases caused by proteotoxicity.

Host: Zhen Chen