In numerous neurodegenerative diseases known collectively as tauopathies, the microtubule-associated protein tau forms fibrillar aggregates that are hallmarks of disease pathology. Tauopathies represent a substantial fraction of diseases associated with protein misfolding. Cellular chaperones known as small heat shock proteins (sHSPs) play a critical role in maintaining protein homeostasis by delaying the onset of protein aggregation. Two sHSPs, HSPB1 (Hsp27) and HSPB5 (αB-crystallin), are constitutively expressed in brain and neurons. Here, we show that HSPB1 and HSPB5 delay tau aggregation in vitro through distinct mechanisms dictated by their disordered N-terminal regions (NTRs). HSPB1 inhibits tau aggregation under normal cellular conditions, whereas HSPB5 displays activity towards tau when activated by stress conditions such as pH acidosis. Using chimeric HSPB1/HSPB5 constructs in which small NTR subregions are swapped, we identify functional regions within the NTRs that modulate chaperone function for tau. The functional regions contain known sites of phosphorylation, suggesting that they are also control points that respond to cellular stress conditions. Our findings support an emerging model in which specific functional motifs within disordered regions of sHSPs govern activity and client engagement under normal and stress conditions.
Keywords: HSPB1; HSPB5; Hsp27; Small heat shock proteins; aB-crystallin; chaperone; intrinsic disorder; protein aggregation; tau aggregation.