Mechanistic insights into the switch of αB-crystallin chaperone activity and self-multimerization.

αB-Crystallin (αBc) is a small heat shock protein that protects cells against abnormal protein aggregation and disease-related degeneration. αBc is also a major structural protein that forms polydisperse multimers that maintain the liquid-like property of the eye lens. However, the relationship and regulation of the two functions have yet to be explored. Here, by combining NMR spectroscopy and multiple biophysical approaches, we found that αBc uses a conserved β4/β8 surface of the central α-crystallin domain to bind α-synuclein and Tau proteins and prevent them from aggregating into pathological amyloids. We noted that this amyloid-binding surface can also bind the C-terminal IPI motif of αBc, which mediates αBc multimerization and weakens its chaperone activity. We further show that disruption of the IPI binding impairs αBc self-multimerization but enhances its chaperone activity. Our work discloses the structural mechanism underlying the regulation of αBc chaperone activity and self-multimerization and sheds light on the different functions of αBc in antagonizing neurodegeneration and maintaining eye lens liquidity.