TY - JOUR TI - Hsp40s play complementary roles in the prevention of tau amyloid formation AU - Irwin, Rose AU - Faust, Ofrah AU - Petrovic, Ivana AU - Wolf, Sharon Grayer AU - Hofmann, Hagen AU - Rosenzweig, Rina A2 - Andreotti, Amy A2 - Dötsch, Volker A2 - Kalodimos, Charalampos Babis VL - 10 PY - 2021 DA - 2021/08/09 SP - e69601 C1 - eLife 2021;10:e69601 DO - 10.7554/eLife.69601 UR - https://doi.org/10.7554/eLife.69601 AB - The microtubule-associated protein, tau, is the major subunit of neurofibrillary tangles associated with neurodegenerative conditions, such as Alzheimer's disease. In the cell, however, tau aggregation can be prevented by a class of proteins known as molecular chaperones. While numerous chaperones are known to interact with tau, though, little is known regarding the mechanisms by which these prevent tau aggregation. Here, we describe the effects of ATP-independent Hsp40 chaperones, DNAJA2 and DNAJB1, on tau amyloid-fiber formation and compare these to the small heat shock protein HSPB1. We find that the chaperones play complementary roles, with each preventing tau aggregation differently and interacting with distinct sets of tau species. Whereas HSPB1 only binds tau monomers, DNAJB1 and DNAJA2 recognize aggregation-prone conformers and even mature fibers. In addition, we find that both Hsp40s bind tau seeds and fibers via their C-terminal domain II (CTDII), with DNAJA2 being further capable of recognizing tau monomers by a second, distinct site in CTDI. These results lay out the mechanisms by which the diverse members of the Hsp40 family counteract the formation and propagation of toxic tau aggregates and highlight the fact that chaperones from different families/classes play distinct, yet complementary roles in preventing pathological protein aggregation. KW - molecular chaperones KW - protein aggregation KW - Hsp40 KW - NMR KW - amyloids KW - tau JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -