Molecular basis for diversification of yeast prion strain conformation

Abstract

Self-propagating β-sheet-rich fibrillar protein aggregates, amyloid fibers, are often associated with cellular dysfunction and disease. Distinct amyloid conformations dictate different physiological consequences, such as cellular toxicity. However, the origin of the diversity of amyloid conformation remains unknown. Here, we suggest that altered conformational equilibrium in natively disordered monomeric proteins leads to the adaptation of alternate amyloid conformations that have different phenotypic effects. We performed a comprehensive high-resolution structural analysis of Sup35NM, an N-terminal fragment of the Sup35 yeast prion protein, and found that monomeric Sup35NM harbored latent local compact structures despite its overall disordered conformation. When the hidden local microstructures were relaxed by genetic mutations or solvent conditions, Sup35NM adopted a strikingly different amyloid conformation, which redirected chaperone-mediated fiber fragmentation and modulated prion strain phenotypes. Thus, dynamic conformational fluctuations in natively disordered monomeric proteins represent a posttranslational mechanism for diversification of aggregate structures and cellular phenotypes.

Proteinase K resistant cores of prions and amyloids

“…Besides, very rarely we observed a structure belonging to two of these Regions, located between residues 81 and 144. A similarly located, but slightly larger, structure was observed in in vitro Sup35 amyloids [49]. It is important to note that the amyloid nature of structures in Region 4 requires further proof.…”

“…In contrast to PrP studies, PK has seen only modest use in the mapping of core sequences in yeast prions. These works studied Ure2 [5], Mod5 [47], hybrid S. cerevisiae-Candida albicans Sup35 [48] and S. cerevisiae Sup35 [16,49]. All these works, except for the last one [16], used in vitro generated self-seeded amyloids of respective proteins.…”

Inert and seed-competent tau monomers suggest structural origins of aggregation

“…This is consistent with our predictions of relative exposure of VQIINK/VQIVYK. The diversity of exposed core elements (almost certainly beyond VQIINK/VQIVYK) could specify the formation of assemblies that give rise to distinct strains, as suggested by work from the Tanaka laboratory 37 . Consistent with this idea, the Fitzpatrick et al study indicates that in AD-derived tau fibrils the VQIVYK sequence plays a key role in the core amyloid structure (along with adjacent amino acids), but the VQIINK sequence does not 38 .…”

“…We note with excitement a recent study of the yeast prion Sup35 from the Tanaka laboratory. Like tau, Sup35 is intrinsically disordered, yet they have observed local structure that influences the conformations of fibrils it can form 37 .…”

Tau monomer encodes strains

“…Nonetheless, based on our characterization of strains derived from M s extracted from the AD and CBD brains, we feel confident in our primary conclusions. In this regard, we were excited to see recent work by Ohhashi et.al, who found that the intrinsically disordered region of Sup35 harbored local compact structure, and also that distinct forms of monomer could give rise to unique Sup35 amyloid conformations (11).…”