I​n malignant cells, the increased and persistent glucose and amino acid uptake to fuel biomass production often creates a microenvironment that is nutrient limited. One cellular response to this change is through the selective degradation of key metabolic enzymes by chaperone-mediated autophagy (CMA). CMA works by recruiting proteins to an Hsc70 chaperone complex, where it assists in the transport and translocation of the targeted protein to the lysosome. Lysosome-mediated degradation of proteins can create an intracellular pool of free amino acids that can be used to fuel other metabolic processes such as nucleotide metabolism.

Recruitment of proteins to Hsc70 for CMA requires the presence of a pentapeptide sequence motif called a CMA Tag. This sequence is present in a large percentage of the proteome; however, the biochemical mechanisms that cause this tag to become exposed for recognition is not fully understood. We hypothesize that post-translational modification- or metabolite-induced allosteric modulation of the protein at distal sites can initiate protein degradation by altering the structural conformation of the targeted protein. We aim to use a combination of biochemical and biophysical approaches to understand the process of metabolic enzyme recruitment to Hsc70 for CMA. Insights gathered from these studies can hopefully spur new directions for how metabolic enzymes can be targeted for therapeutic benefit.