Amyloid-like fibrils of ribonuclease A with three-dimensional domain-swapped and native-like structure

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Abstract
Amyloid or amyloid-like fibrils are elongated, insoluble protein aggregates, formed in vivo1 in association with neurodegenerative diseases or in vitro2 from soluble native proteins, respectively. The underlying structure of the fibrillar or ‘cross-β’ state has presented long-standing, fundamental puzzles of protein structure. These include whether fibril-forming proteins have two structurally distinct stable states, native and fibrillar, and whether all or only part of the native protein refolds as it converts to the fibrillar state. Here we show that a designed amyloid-like fibril of the well-characterized enzyme RNase A contains native-like molecules capable of enzymatic activity. In addition, these functional molecular units are formed from a core RNase A domain and a swapped complementary domain. These findings are consistent with the zipper-spine model3 in which a cross-β spine is decorated with three-dimensional domain-swapped functional units, retaining native-like structure.