Structural highlights
Publication Abstract from PubMedAffilin proteins, artificial binding proteins based on the ubiquitin scaffold, have been generated by directed protein evolution to yield de-novo variants that bind the extra-domain B (EDB) of oncofetal fibronectin, an established marker of tumor neovasculature. The crystal structures of two EDB-specific Affilin variants reveal a striking structural plasticity of the ubiquitin scaffold, characterised by beta-strand slippage, leading to different negative register shifts of the beta5 strands. This process recruits amino acid residues from beta5 towards the N-terminus to an adjacent loop region and subsequent residues into beta5, respectively, remodeling the binding interface and leading to target specificity and affinity. Protein backbone alterations resulting from beta-strand register shifts, as seen in the ubiquitin fold, can pose additional challenges to protein engineering as structural evidence of these events is still limited and they are difficult to predict. However, they can surface under the selection pressure of directed evolution and suggest that backbone plasticity allowing beta-strand slippages can increase structural diversity, enhancing the evolutionary potential of a protein scaffold. Ubiquitin-derived artificial binding proteins targeting oncofetal fibronectin reveal scaffold plasticity by beta-strand slippage.,Katzschmann A, Haupts U, Reimann A, Settele F, Gloser-Braunig M, Fiedler E, Parthier C Commun Biol. 2024 Jul 27;7(1):907. doi: 10.1038/s42003-024-06569-9. PMID:39068227[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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