Functions of the Proteasome From Protein Degradation to Disease Therapy

A webinar for the COST Proteostasis Group - a European network to integrate research on intracellular proteolysis pathways in health and disease.
Learn more about proteasomes at www.rndsystems.com/research-a...
Recorded on 4th February 2016 with Prof. Alfred Goldberg, Harvard Medical School.
The 26S proteasome is the primary site for protein degradation in cells. This 60-subunit molecular machine selectively destroys misfolded, potentially toxic proteins and most regulatory proteins. Such proteins are first marked for proteasomal destruction by attachment of a chain of ubiquitin molecules. Dr. Goldberg will discuss the proteasome’s complex multistep mechanism by which it degrades ubiquitinated proteins to small peptides and also the development of the proteasome inhibitors, which are widely used as research tools (MG132), but some (Bortezomib) are used in the treatment of the hematologic cancers. These agents have dramatically improved the survival of patients with multiple myeloma, but cells eventually become resistant in part by increasing expression of new proteasomes. Recent studies indicate that proteasome function is also tightly regulated. The binding of an ubiquitinated substrate activates the proteasome by stimulating multiple steps in proteolysis (e.g. ATP hydrolysis). In addition proteasome activity can be stimulated by phosphorylation of a 19S subunit by Protein Kinase A. Agents that raise cAMP and activate PKA in cells promote the clearance of misfolded proteins, including aggregation-prone proteins, that cause neurodegenerative disease. Thus, pharmacological agents that activate the proteasome may have therapeutic benefits against proteotoxic diseases.

[@russelmiller7311]

The proteasome is a multisubunit enzyme complex that plays a central role in the regulation of proteins that control cell-cycle progression and apoptosis, and has therefore become an important target for anticancer therapy. Before a protein is degraded, it is first flagged for destruction by the ubiquitin conjugation system, which ultimately results in the attachment of a polyubiquitin chain on the target protein.-Reference from www.bocsci.com/tag/proteasome-315.html

[@InquilineKea]

wow, chymotrypsin-like cleavage (beta5) might be most important for longevity
34:37
"key lysine residue" at 27:00?