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Publication Abstract from PubMed

The crystal structures of six different fibronectin type III consensus derived Tencon domains, whose solution properties exhibit no, to various degrees of, aggregation according to SEC, have been determined. The structures of the five variants showing aggregation reveal 3D domain swapped dimers. In all five cases, the swapping involves the C-terminal beta-strand resulting in the formation of Tencon dimers in which the target-binding surface is blocked. All of the variants differ in sequence in the FG loop, which is the hinge loop in the beta-strand-swapped dimers. The six tencon variants have between 0 and 5 residues inserted between positions 77 and 78 in the FG loop. Analysis of the structures suggests that a non-glycine residue at position 77 and insertions of less than 4 residues may destabilize the beta-turn in the FG loop promoting beta-strand swapping. Swapped dimers with an odd number of inserted residues may be less stable, particularly if they contain proline residues, because they cannot form perfect beta-bridges in the FG regions that link the swapped dimers. The Tencon beta-swapped variants with the longest FG sequences are observed to form higher order hexameric or helical oligomeric structures in the crystal correlating well with the aggregation properties of these domains observed in solution. Understanding the structural basis for domain-swapped dimerization and oligomerization will support engineering efforts of the Tencon domain to produce variants with desired biophysical properties. (c) Proteins 2013;. (c) 2013 Wiley Periodicals, Inc.

C-Terminal beta-strand swapping in a consensus derived fibronectin type III scaffold.,Teplyakov A, Obmolova G, Malia TJ, Luo J, Jacobs SA, Chan W, Domingo D, Baker A, O'Neil KT, Gilliland GL Proteins. 2013 Dec 23. doi: 10.1002/prot.24502. PMID:24375666^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.