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

TitleNMR spectroscopy reveals a preferred conformation with a defined hydrophobic cluster for polyglutamine binding peptide 1
Authors
KeywordsAmyloid inhibitor
Nuclear magnetic resonance
CAG-expansion diseases
Protein misfolding & aggregation
Issue Date2014
Citation
Archives of Biochemistry and Biophysics, 2014, v. 558, p. 104-110 How to Cite?
AbstractSeveral 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-NH 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. 3 +
Persistent Identifierhttp://hdl.handle.net/10722/299511
ISSN
2023 Impact Factor: 3.8
2023 SCImago Journal Rankings: 0.888
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorRamos-Martín, Francisco-
dc.contributor.authorHervás, Rubén-
dc.contributor.authorCarrión-Vázquez, Mariano-
dc.contributor.authorLaurents, Douglas V.-
dc.date.accessioned2021-05-21T03:34:34Z-
dc.date.available2021-05-21T03:34:34Z-
dc.date.issued2014-
dc.identifier.citationArchives of Biochemistry and Biophysics, 2014, v. 558, p. 104-110-
dc.identifier.issn0003-9861-
dc.identifier.urihttp://hdl.handle.net/10722/299511-
dc.description.abstractSeveral 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-NH 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. 3 +-
dc.languageeng-
dc.relation.ispartofArchives of Biochemistry and Biophysics-
dc.subjectAmyloid inhibitor-
dc.subjectNuclear magnetic resonance-
dc.subjectCAG-expansion diseases-
dc.subjectProtein misfolding & aggregation-
dc.titleNMR spectroscopy reveals a preferred conformation with a defined hydrophobic cluster for polyglutamine binding peptide 1-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.abb.2014.06.025-
dc.identifier.pmid25009140-
dc.identifier.scopuseid_2-s2.0-84905030325-
dc.identifier.volume558-
dc.identifier.spage104-
dc.identifier.epage110-
dc.identifier.eissn1096-0384-
dc.identifier.isiWOS:000340701600013-

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