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May 2012 research highlights

A glimpse at toxicity

SBKB [doi:10.1038/nsmb.2280]

A crystallographic study provides a structural model for toxic amyloid oligomers.

Emerging evidence suggests that the toxic forms of amyloid-forming proteins are small amyloid oligomers, not amyloid fibrils. These oligomers are transient, making them difficult to characterize, but they have been described as β-sheet rich. In an effort to gain insight into small amyloid oligomers, Eisenberg, Laganowsky and colleagues have identified an oligomer-forming hairpin loop in the amyloid-forming protein αB-crystallin (ABC). A six-residue peptide (G6V), an 11-residue peptide (K11V) and a tandem repeat of K11V (K11V-TR), all derived from the hairpin loop, form amyloid fibrils when agitated at high temperature. Under normal solution conditions, K11V and K11-VTR formed hexamers and trimers, respectively. Like other small amyloid oligomers, these oligomers were toxic and were recognized by the conformational antibody A11. The crystal structures of K11V and K11V-TR reveal six-stranded antiparallel β-barrel cylinders ('cylindrins'), differing from the native ABC structure and the β-sheet steric zipper formed by G6V. The cylindrins share some features of the steric zippers, having backbone-mediated hydrogen bonds and shape-complementary packing interactions at strand interfaces. However, the cylindrin strands are tilted and, when unrolled into a β-sheet, out of register. The β-strands in amyloid fibrils and steric zippers are in register, and a transition from a cylindrin-like oligomer to a fibril would be energetically costly. Although this suggests that cylindrin is off pathway to fibril formation, a β-amyloid sequence could also be modeled with a cylindrin structure, providing additional support for cylindrin-type models of amyloid oligomers. (Science 335, 1228–1231, 2012)

Michelle Montoya

 

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