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© Research
Publication : Proceedings of the National Academy of Sciences of the United States of America

Structural and molecular basis of cross-seeding barriers in amyloids.

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Proceedings of the National Academy of Sciences of the United States of America - 05 Jan 2021

Daskalov A, Martinez D, Coustou V, El Mammeri N, Berbon M, Andreas LB, Bardiaux B, Stanek J, Noubhani A, Kauffmann B, Wall JS, Pintacuda G, Saupe SJ, Habenstein B, Loquet A,

Link to Pubmed [PMID] – 33443172

Link to DOI – e201408511810.1073/pnas.2014085118

Proc Natl Acad Sci U S A 2021 Jan; 118(1):

Neurodegenerative disorders are frequently associated with β-sheet-rich amyloid deposits. Amyloid-forming proteins can aggregate under different structural conformations known as strains, which can exhibit a prion-like behavior and distinct pathophenotypes. Precise molecular determinants defining strain specificity and cross-strain interactions (cross-seeding) are currently unknown. The HET-s prion protein from the fungus Podospora anserina represents a model system to study the fundamental properties of prion amyloids. Here, we report the amyloid prion structure of HELLF, a distant homolog of the model prion HET-s. We find that these two amyloids, sharing only 17% sequence identity, have nearly identical β-solenoid folds but lack cross-seeding ability in vivo, indicating that prion specificity can differ in extremely similar amyloid folds. We engineer the HELLF sequence to explore the limits of the sequence-to-fold conservation and to pinpoint determinants of cross-seeding and prion specificity. We find that amyloid fold conservation occurs even at an exceedingly low level of identity to HET-s (5%). Next, we derive a HELLF-based sequence, termed HEC, able to breach the cross-seeding barrier in vivo between HELLF and HET-s, unveiling determinants controlling cross-seeding at residue level. These findings show that virtually identical amyloid backbone structures might not be sufficient for cross-seeding and that critical side-chain positions could determine the seeding specificity of an amyloid fold. Our work redefines the conceptual boundaries of prion strain and sheds light on key molecular features concerning an important class of pathogenic agents.

https://pubmed.ncbi.nlm.nih.gov/33443172