title: NMR spectroscopy reveals a preferred conformation with a defined hydrophobic cluster for polyglutamine binding peptide 1.
abstract: Several 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.
authors.affiliation: Instituto Cajal, IC-Consejo Superior de Investigaciones Científicas, Avda. Doctor Arce 37, E-28002 Madrid, Spain; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), E-28049 Cantoblanco, Madrid, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Ramos-Martín
authors.affiliation: Instituto Cajal, IC-Consejo Superior de Investigaciones Científicas, Avda. Doctor Arce 37, E-28002 Madrid, Spain; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), E-28049 Cantoblanco, Madrid, Spain.
authors.forename: Rubén
authors.initials: R
authors.lastname: Hervás
authors.affiliation: Instituto Cajal, IC-Consejo Superior de Investigaciones Científicas, Avda. Doctor Arce 37, E-28002 Madrid, Spain; Instituto Madrileño de Estudios Avanzados en Nanociencia (IMDEA-Nanociencia), E-28049 Cantoblanco, Madrid, Spain.
authors.forename: Mariano
authors.initials: M
authors.lastname: Carrión-Vázquez
authors.affiliation: Instituto de Química Física "Rocasolano", Consejo Superior de Investigaciones Científicas, Serrano 119, Madrid E-28006, Spain. Electronic address: dlaurents@iqfr.csic.es.
authors.forename: Douglas V
authors.initials: DV
authors.lastname: Laurents
mesh_terms: D000595:Amino Acid Sequence; D057927:Hydrophobic and Hydrophilic Interactions; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry*; D011487:Protein Conformation
chemical_list: D009842:Oligopeptides; C407346:polyglutamine-binding protein 1
keywords: Amyloid inhibitor; CAG-expansion diseases; Nuclear magnetic resonance; Protein misfolding & aggregation