title: Targeting Protein-Protein Interactions in the Proteasome Super-Assemblies.
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 proteasome-targeting 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.
authors.affiliation: Department of Molecular Medicine, Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78245; USA. gaczynska@uthscsa.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Gaczynska
authors.forename: Pawel A
authors.initials: PA
authors.lastname: Osmulski
mesh_terms: D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000737:chemistry*; D000069286:Bortezomib / Q000737:chemistry; D020134:Catalytic Domain; D015195:Drug Design; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D020123:Sirolimus / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009842:Oligopeptides; D010455:Peptides; D000069286:Bortezomib; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex; D020123:Sirolimus