Asst. Professor Andreas (Andy) Martin
Biochemistry, Biophysics and Structural Biology
University of California @ Berkeley
Berkeley, CA

Monday, October 20, 2014
3:00 pm (CT)
3269 Beckman Institute

Abstract

The eukaryotic 26S proteasome utilizes a complex set of coordinated processing steps for the ATP-dependent degradation of ubiquitin-tagged substrates. Our structure-function studies reveal important features and conformational changes of the proteasome regulatory particle that facilitate substrate binding, engagement, deubiquitination, and unfolding. Systematic mutational analyses of the proteasome ATPase ring, using a heterologous expression system and in-vitro reconstitution of 26S holoenzymes, indicate that the six ATPase subunits play distinct roles in substrate engagement and translocation. Optical tweezers single-molecule studies of a related protease, ClpXP, suggest a coordinated ATP-hydrolysis mechanism in the ATPase ring to drive mechanical unfolding and processive translocation of substrates into the associated peptidase for degradation. Furthermore, structural and mutational studies of the proteasomal deubiquitinating subunit Rpn11 provide new mechanistic insights into the translocation-dependence and regulation of substrate deubiquitination.