8peq
From Proteopedia
Complex of diubiquitin-derived artificial binding protein (Affilin) variant Af2 with its target oncofetal fibronectin (fragment 7B8)
Structural highlights
DiseaseFINC_HUMAN Defects in FN1 are the cause of glomerulopathy with fibronectin deposits type 2 (GFND2) [MIM:601894; also known as familial glomerular nephritis with fibronectin deposits or fibronectin glomerulopathy. GFND is a genetically heterogeneous autosomal dominant disorder characterized clinically by proteinuria, microscopic hematuria, and hypertension that leads to end-stage renal failure in the second to fifth decade of life.[1] FunctionFINC_HUMAN Fibronectins bind cell surfaces and various compounds including collagen, fibrin, heparin, DNA, and actin. Fibronectins are involved in cell adhesion, cell motility, opsonization, wound healing, and maintenance of cell shape.[2] [3] [4] [5] Anastellin binds fibronectin and induces fibril formation. This fibronectin polymer, named superfibronectin, exhibits enhanced adhesive properties. Both anastellin and superfibronectin inhibit tumor growth, angiogenesis and metastasis. Anastellin activates p38 MAPK and inhibits lysophospholipid signaling.[6] [7] [8] [9] 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[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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