Proteostasis, Chaperones & Protein Degradation

Protein homeostasis, or proteostasis, refers to the ability of cells to properly regulate the synthesis, folding, trafficking and degradation of cellular proteins, and is often dysregulated in cancer and other diseases.

Of particular interest to scientists at Ranok Therapeutics are the roles played in proteostasis by complexes composed of chaperone and co-chaperone proteins. Chaperones mediate the proper folding, stability and/or activation states of their substrate proteins. These substrates include many key cellular regulatory proteins, such as growth factor receptors, protein kinases and transcription factors. Importantly, mutations that have been implicated in the development of cancer are often found in chaperone substrates. Stabilization of such aberrant oncoproteins by chaperones can prevent their degradation and promote the growth and survival of cancer cells.

In some cases, chaperones can also recognize misfolded proteins and direct them towards degradation by the ubiquitin-proteasome system (UPS). The UPS is a major cellular pathway mediating the disposal of unwanted proteins. This occurs by the process of ubiquitination, when a chain of small ubiquitin proteins are attached to a substrate protein by an E2 ubiquitin-conjugating enzyme and one of several hundred different E3 ubiquitin ligase enzymes. Such ubiquitin-tagged proteins can then be delivered to the proteasome for degradation and metabolic recycling. The ability of some chaperones to direct proteins towards the UPS is facilitated by their direct interaction with many different E3 ubiquitin ligases.

Ranok’s proprietary CHAMP™ platform technology is based on our founder’s extensive background in proteostasis research.