Function within Disorder: HSPB1 and HSPB5 Modulate Tau Aggregation

Abstract

In numerous neurogenerative diseases, microtubule-associated protein tau forms fibrillar aggregates that are hallmarks of disease pathology. Small heat shock proteins (sHSPs) are ATP-independent molecular chaperones that play a critical role in maintaining protein homeostasis. Two sHSPs, HSPB1 (Hsp27) and HSPB5 (aB-crystallin), are constitutively expressed in the brain and neurons. Here, we show that HSPB1 and HSPB5 delay tau aggregation in vitro through distinct mechanisms determined by their disordered N-terminal regions (NTRs). HSPB1 inhibits tau aggregation under non-stress conditions, whereas HSPB5 requires activation by pH acidosis. Using chimeric constructs in which small NTR subregions are swapped, we identify different functional regions within the NTRs that modulate chaperone function for tau. The regionsidentified contain known sites of phosphorylation, suggesting that they are also functional control points that respond to cellular stress conditions. To further define how NTR sequence features encode function, NTR-ACD interaction network is perturbed through domain swaps, mutation, and hetero-oligomerization. Our findings support a model in which specific functional motifs within disordered NTRs of sHSPs govern activity and client preference in response to cellular stress. Finally, this thesis presents a systematic framework for organizing sHSP NTRs into five distinct Function Regions (FR-A through FR-E) across ten human sHSPs. This work also establishes experimental tools for understanding sHSP oligomerization and function.