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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 (\u03b1B\u2010crystallin), are constitutively expressed in the brain and neurons. Here, we show that HSPB1 and HSPB5 delay tau aggregation in vitro through distinct mechanisms dictated by their disordered N\u2010terminal regions (NTRs). HSPB1 inhibits tau aggregation under normal cellular conditions, whereas HSPB5 displays activity toward 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.<\/jats:p>","DOI":"10.1002\/pro.70780","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T12:29:01Z","timestamp":1789561741000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Function within disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation"],"prefix":"10.1002","volume":"35","author":[{"given":"Mia","family":"Cervantes","sequence":"first","affiliation":[{"name":"Department of Biochemistry, School of Medicine University of Washington  Seattle Washington USA"},{"name":"Department of Medicinal Chemistry, School of Pharmacy University of Washington  Seattle Washington USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria 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