Fig. 8.

Different activities of Bri2 BRICHOS are mediated by distinct quaternary structures. a Bri2 BRICHOS monomers form dimers, which are able to assemble into structured high-molecular weight oligomers. Each quaternary structure most efficiently exerts one distinct function: monomers prevent Aβ42-associated neurotoxicity, dimers counteract Aβ42 fibrillization and oligomers inhibit non-fibrillar aggregation. The aggregation behavior of Aβ is governed by different microscopic nucleation events, where in particular fibril end elongation (k ₊) and surface-catalyzed secondary nucleation (k ₂) are inhibited by Bri2 BRICHOS dimers. b The efficiencies in inhibiting neurotoxicity (z-axis), Aβ42 fibrillization (y-axis) and non-fibrillar aggregation (x-axis), derived from data in Figs. 4–6, are plotted for each quaternary structure species. The diversity in functions fits with molecular sizes of the respective Bri2 BRICHOS quaternary structure compared with the sizes of their respective preferred substrate. A Bri2 BRICHOS dimer (surface area ~ 2570 Ų, evaluated by juxtaposing two Bri2 BRICHOS subunit models²⁶, built from the proSP-C BRICHOS crystal structure (PDB 2YAD)) matches well the cross-sectional area (~ 2250 Ų) of Aβ42 fibrils (PDB 5KK3) that consist of two β-structured Aβ molecules per fibril layer. A Bri2 BRICHOS monomer, which prevents Aβ toxicity to neuronal networks, fits well in size with single layer β-structured Aβ molecules that may build up oligomers. A high-molecular weight Bri2 BRICHOS oligomer (Fig. 2) that efficiently suppresses thermo-induced aggregation of CS provides a large binding surface that is suited to capture native and/or partially denatured CS (illustrated by the structure of porcine heart CS, PDB 3ENJ)