Title:Targeting Protein-Protein Interactions in the Proteasome Super-Assemblies.
Volume: 15
Issue: 20
Author(s): Maria Gaczynska and Pawel A. Osmulski
Affiliation:
Keywords:
Allostery, Cancer, Drugs, Inhibitors, Proteasome, Protein-protein interactions, Proteolysis, Ubiquitin-proteasome
pathway.
Abstract: Protein-protein interactions (PPI) are at the center of molecular mechanisms of life. The
protein ligands convene for regulation of biological function: adding, enhancing or inhibiting activity,
for assistance in structural integrity or to enable subsequent PPI. All these general roles of PPI are represented
in the proteasome, the giant proteolytic factory universally present in human cells. The proteasome
is a renowned target for anti-cancer drugs and a considered target for drugs curbing inflammation.
The essential function of the proteasome, the degradation of a majority of intracellular proteins
via the ubiquitin-proteasome pathway, relies on proper interactions between multiple subunits of
the enzyme and between multiple modules forming distinct super-assemblies covered by the “proteasome” name. The interface
regions between constitutive, alternative or transient protein components of the proteasome provide a rich platform
for design of drugs with potentially very diverse actions. Still, the resource remains largely untapped since all proteasometargeting
drugs used so far in humans are classical competitive inhibitors blocking catalytic centers. In this review, we
will discuss the opportunities and challenges of targeting PPI in the hub enzyme for intracellular protein catabolism, the
proteasome.
