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NMR spectroscopy reveals a preferred conformation with a defined hydrophobic cluster for polyglutamine binding peptide 1

AutorRamos-Martín, F.; Hervás, Rubén.; Carrión-Vázquez, Mariano Sixto ; Laurents, D.V.
Fecha de publicación2014
EditorAcademic Press
CitaciónArchives of Biochemistry and Biophysics 558: 104- 110 (2014)
ResumenSeveral important human inherited neurodegenerative diseases are caused by >polyQ expansions>, which are aberrant long repeats of glutamine residues in proteins. PolyQ binding peptide 1 (QBP1), whose minimal active core sequence is Trp-Lys-Trp-Trp-Pro-Gly-Ile-Phe, binds to expanded polyQs and blocks their β-structure transition, aggregation and in vivo neurodegeneration. Whereas QBP1 is a widely used, commercially available product, its structure is unknown. Here, we have characterized the conformations of QBP1 and a scrambled peptide (Trp-Pro-Ile-Trp-Lys-Gly-Trp-Phe) in aqueous solution by CD, fluorescence and NMR spectroscopies. A CD maximum at 227 nm suggests the presence of rigid Trp side chains in QBP1. Based on 41 NOE-derived distance constraints, the 3D structure of QBP1 was determined. The side chains of Trp 4 and Ile 7, and to a lesser extent, those of Lys 2, Trp 3 and Phe 8, form a small hydrophobic cluster. Pro 5 and Gly 6 adopt a type II tight turn and Lys 2's ζ-NH3 + is positioned to form a favorable cation-π interaction with Trp 4's indole ring. In contrast, the scrambled QBP1 peptide, which lacks inhibitory activity, does not adopt a preferred structure. These results provide a basis for future structure-based design approaches to further optimize QBP1 for therapy. © 2014 Elsevier Inc. All rights reserved.
URIhttp://hdl.handle.net/10261/167792
Identificadoresdoi: 10.1016/j.abb.2014.06.025
issn: 1096-0384
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