Bridging structure and selectivity in chaperone-mediated autophagy: towards targeted therapeutics

Chaperone-mediated autophagy (CMA) is a pivotal cellular process essential for maintaining homeostasis by selectively degrading damaged or non-essential proteins, and its impairment is associated with numerous diseases. The allure of CMA lies in its selectivity, a trait that holds the potential of revolutionising healthcare, offering superior therapies and paving the way for a future in which drug resistance is conquered. Thus, understanding the factors that dictate selectivity in the pathway is indispensable. CMA degrades only a subset of proteins, and its selectivity is regulated by two key proteins, namely heat shock cognate 71 kDa protein (HSPA8; also known as Hsc70) and lysosome-associated membrane protein 2A (LAMP2A). However, structural insights into these proteins, which are responsible for CMA functionality, are still in their infancy. We collated literature in search of answering unresolved questions, such as: what unique structural cues mark a protein as a CMA target? How does the Hsc70 along with co-chaperones decipher these cues? Where does Hsc70 bind to its co-chaperone? What is the substrate binding site in Hsc70, and how does the Hsc70-substrate complex bind to LAMP2A? What are the structural secrets governing LAMP2A's assembly into multimers and its role in shuttling substrates to the lysosome? Although direct answers to some of these questions are currently elusive due to the absence of experimental structures of selectively bound complexes, we have collated existing information to assess their potential resolution. Additionally, we review current structural insights into the therapeutic strategies targeting these proteins and the pathway. Comprehension unveils potential avenues for therapeutic innovation.