A conserved histidine modulates HSPB5 structure to trigger chaperone activity in response to stress-related acidosis

Proteins are composed of one or more long chain-like molecules that must fold into complex three-dimensional shapes in order to work properly. Incorrectly folded proteins cannot function and often aggregate into toxic states that are associated with a number of neurological diseases including Alzheimer's, Huntington's, and Parkinson's. Elevated temperatures, increased acidity, and other stressful conditions in the cell can hinder the folding process and may cause existing proteins to unfold and aggregate. However, when cells experience these stresses, certain proteins—known as small heat shock proteins (or sHSPs for short)—act as ‘holdase chaperones’ to protect cells from protein misfolding. HSPB5 is one such chaperone that binds to and stabilizes other proteins (called ‘clients’) to prevent their aggregation. The core structure of HSPB5 and other similar chaperone proteins is well known. But, it is not clear how chaperones sense stressful conditions and respond to increase their activity to help stabilize client proteins. Now, Rajagopal et al. have identified a single amino acid in HSPB5 that is sensitive to pH changes. When the environment inside a cell becomes more acidic, this amino acid (a histidine) triggers changes in HSPB5's structure that enhance the chaperone's activity. This histidine was then replaced with another amino acid in an attempt to lock HSPB5 into a low-pH state that mimics an active HSPB5 chaperone inside a stressed cell. Further experiments revealed that this mutant HSPB5 is a super-active holdase chaperone, and that it dramatically changes its structure to bind to a client protein in the holdase state. From this, Rajagopal et al. propose a model to explain how cellular stress triggers small changes in HSPB5 that propagate through the chaperone in a response mechanism that increases its activity. Future studies will investigate whether inherited mutations in HSPB5 and other similar chaperones—which are associated with cardiac, muscle, and nerve disorders—exert their effect by disrupting this response mechanism.