Evolution and Design of Protein Structure by Folding Nucleus Symmetric Expansion

• Published in: Structure (London) 2014-10, Vol.22 (10), p.1377-1384
• Main Authors: Longo, Liam M., Kumru, Ozan S., Middaugh, C. Russell, Blaber, Michael
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Calorimetry, Differential Scanning; Crystallography, X-Ray; Design engineering; Evolution; Evolution, Molecular; Evolutionary; Folding; Genes; Models, Molecular; Molecular Sequence Data; Nuclei; Protein Conformation; Protein Denaturation; Protein Folding; Proteins; Proteins - chemistry; Reproduction
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2014.08.008

Models of symmetric protein evolution typically invoke gene duplication and fusion events, in which repetition of a structural motif generates foldable, stable symmetric protein architecture. Success of such evolutionary processes suggests that the duplicated structural motif must be capable of nucleating protein folding. If correct, symmetric expansion of a folding nucleus sequence derived from an extant symmetric fold may be an elegant and computationally tractable solution to de novo protein design. We report the efficient de novo design of a β-trefoil protein by symmetric expansion of a β-trefoil folding nucleus, previously identified by ɸ-value analysis. The resulting protein, having exact sequence symmetry, exhibits superior folding properties compared to its naturally evolved progenitor—with the potential for redundant folding nuclei. In principle, folding nucleus symmetric expansion can be applied to any given symmetric protein fold (that is, nearly one-third of the known proteome) provided information of the folding nucleus is available. [Display omitted] •A folded β-trefoil protein was designed by symmetric expansion of a folding nucleus•The β-trefoil protein is more stable, less aggregation prone, than its progenitor•Folding nucleus symmetric expansion (FNSE) is an efficient approach to protein design•FNSE may be applied to any symmetric protein fold (∼one-third of known architectures) Longo et al. use folding nucleus symmetric expansion (FNSE) for the de novo design of a β-trefoil protein by symmetric expansion of a β-trefoil folding nucleus. The resulting protein is more stable than its progenitor. FNSE is an efficient approach to protein design and may be applicable to any symmetric protein fold.