From common sequence to diverse strains

In this study we reveal the thermodynamic principles that govern how amyloid fibrils form, mature, and diversify across diseases. By combining high-resolution cryo-EM structural time series with residue-level energetic profiling, we show that amyloid fibrils from three very different proteins (IAPP, tau, and α-synuclein) follow a shared biophysical logic during assembly. In all three systems, short aggregation-prone regions (APRs) function as powerful, sequence-encoded “stabilizing motifs” that anchor the fibril core. As assembly progresses, these APRs reorganize and expand, while surrounding regions accumulate structural frustration that provides the flexibility needed to generate distinct polymorphic states.

We further uncover how external factors, such as metal ions in tau fibrils or polyanions in α-synuclein, selectively stabilize local regions of strain that would otherwise be energetically unfavorable. These cofactors help explain why certain polymorphs emerge only in specific contexts and why some in vitro structures differ from those found in disease tissue. By showing where and how such compensatory interactions occur, this work offers a mechanistic view of how intrinsic sequence constraints and extrinsic environmental influences cooperate to shape fibril architecture.

Together, these findings shift the view of amyloid polymorphs from static end-states to thermodynamic outcomes of defined maturation pathways. By mapping how stabilizing APRs and frustrated regions evolve, and where cofactors redistribute strain, we reveal common rules that govern strain emergence across proteins. This framework explains how fibrils diversify in different disease contexts and highlights new points where their stability and pathogenic properties can be modulated.

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