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Sequestration of a β‐Hairpin for Control of α‐Synuclein Aggregation
Author(s) -
Mirecka Ewa A.,
Shaykhalishahi Hamed,
Gauhar Aziz,
Akgül Şerife,
Lecher Justin,
Willbold Dieter,
Stoldt Matthias,
Hoyer Wolfgang
Publication year - 2014
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201309001
Subject(s) - synucleinopathies , alpha synuclein , fibril , chemistry , amyloid (mycology) , biophysics , protein aggregation , sequence (biology) , synuclein , amyloid fibril , protein folding , biochemistry , parkinson's disease , biology , amyloid β , disease , medicine , pathology , inorganic chemistry
The misfolding and aggregation of the protein α‐synuclein (α‐syn), which results in the formation of amyloid fibrils, is involved in the pathogenesis of Parkinson’s disease and other synucleinopathies. The emergence of amyloid toxicity is associated with the formation of partially folded aggregation intermediates. Here, we engineered a class of binding proteins termed β‐wrapins (β‐wrap proteins) with affinity for α‐synuclein (α‐syn). The NMR structure of an α‐syn:β‐wrapin complex reveals a β‐hairpin of α‐syn comprising the sequence region α‐syn(37–54). The β‐wrapin inhibits α‐syn aggregation and toxicity at substoichiometric concentrations, demonstrating that it interferes with the nucleation of aggregation.