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J Mol Biol. 2011 Apr 15;407(5):744-63. doi: 10.1016/j.jmb.2011.02.002. Epub 2011 Feb 16.

A polypeptide "building block" for the β-trefoil fold identified by "top-down symmetric deconstruction".

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Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL 32306-4300, USA.


Fibroblast growth factor-1, a member of the 3-fold symmetric β-trefoil fold, was subjected to a series of symmetric constraint mutations in a process termed "top-down symmetric deconstruction." The mutations enforced a cumulative exact 3-fold symmetry upon symmetrically equivalent positions within the protein and were combined with a stability screen. This process culminated in a β-trefoil protein with exact 3-fold primary-structure symmetry that exhibited excellent folding and stability properties. Subsequent fragmentation of the repeating primary-structure motif yielded a 42-residue polypeptide capable of spontaneous assembly as a homotrimer, producing a thermostable β-trefoil architecture. The results show that despite pronounced reduction in sequence complexity, pure symmetry in the design of a foldable, thermostable β-trefoil fold is possible. The top-down symmetric deconstruction approach provides a novel alternative means to successfully identify a useful polypeptide "building block" for subsequent "bottom-up" de novo design of target protein architecture.

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