Yeast prions are protein-based heritable elements, most of which are amyloid aggregates of functional proteins. Their propagation in cell populations is dependent upon an aggregate-fragmentation mechanism involving a core set of chaperone proteins including the J-protein/Hsp40 Sis1, Hsp70s, and Hsp104. These same chaperones can also act to eliminate prions via another, less well-resolved mechanism. Prions can also exist as distinct amyloid structural polymorphisms, called ‘strains’ in mammalian systems and ‘variants’ in yeast. Recently we and others have uncovered significant complexity in the chaperone interactions among various yeast prions and prion variants, demonstrating that, in contrast to Hsp104 and Hsp70, which have general roles, J-proteins represent a prion-specific component of the prion-propagation/elimination machinery. Most notable has been a direct demonstration that the persistence of alternative conformations of prions is dependent on the action of different molecular chaperones. Because J-proteins often act as targeting factors for Hsp70s, they may constitute the first chaperone response to the presence of amyloid, but a critical barrier to advancing the understanding of chaperone function in prion biology is that the fundamental chaperone interactions for most yeast prions remain unidentified, precluding a comprehensive understanding of how protein sequences give rise to amyloids with distinct patterns of chaperone interaction. Here we will present our latest undergraduate-generated data regarding: 1) the unusual role of the J-protein Apj1 in the elimination of only some prions, and 2) the conservation of the prion-maintaining J-protein functions of Sis1 in plants. These findings suggest that amyloid structures of alternative prion conformations have unique features that are differentiable by chaperone proteins, revealing a previously unappreciated level of additional complexity that may be exploitable for therapeutic intervention.

Elucidating the prion-chaperone interaction network in yeast: prion-specific chaperone functions both promote and limit amyloid diversity

ACS Spring 2022

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