Emergence of fractal geometries in the evolution of a metabolic enzyme.

Fractals are patterns that are self-similar across multiple length-scales1. Macroscopic fractals are common in nature2-4; however, so far, molecular assembly into fractals is restricted to synthetic systems5-12. Here we report the discovery of a natural protein, citrate synthase from the cyanobacterium Synechococcus elongatus, which self-assembles into Sierpinski triangles. Using cryo-electron microscopy, we reveal how the fractal assembles from a hexameric building block. Although different stimuli modulate the formation of fractal complexes and these complexes can regulate the enzymatic activity of citrate synthase in vitro, the fractal may not serve a physiological function in vivo. We use ancestral sequence reconstruction to retrace how the citrate synthase fractal evolved from non-fractal precursors, and the results suggest it may have emerged as a harmless evolutionary accident. Our findings expand the space of possible protein complexes and demonstrate that intricate and regulatable assemblies can evolve in a single substitution.

His6, His13, and His14 residues in Aß 1-40 peptide significantly and specifically affect oligomeric equilibria.

Oligomers of Aß peptide are implicated as the most probable causative agent in Alzheimer's disease. However, their structural properties remain elusive due to the dynamic and heterogeneous character of oligomeric species coexisting in solution. Nevertheless, new approaches, mainly based on mass spectrometry, provide unique access to these different structural forms. Using these methods, we previously showed that the N-terminal, non-amyloidogenic region of Aß is involved in the network of interactions specifically stabilizing oligomers. In the present study, we identified three histidine residues as active participants in this network. Detailed knowledge of the structural features that are potentially important for oligomer-mediated neurotoxicity is a prerequisite for the rational design of oligomerization modifiers.