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-' 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- spine is decorated with three-dimensional domain-swapped functional units, retaining native-like structure.

1. Howard Hughes Medical Institute, UCLA-DOE Institute for Genomics and Proteomics, Box 951570, UCLA, Los Angeles, California 90095-1570, USA
2. †Present address: Division of Chemistry and Chemical Engineering, Caltech, Pasadena, California 91125, USA

Correspondence to: David Eisenberg¹ Correspondence and requests for materials should be addressed to D.E. (Email: david@mbi.ucla.edu). The structure of Q10-H119A RNase A has been deposited in the Protein Data Bank with accession code 2APQ. The model of Fig. 4 has been deposited in the Protein Data Bank with accession code 2APU.

Received 18 January 2005; Accepted 16 June 2005

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