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Monitoring and Targeting the Initial Dimerization Stage of Amyloid Self‐Assembly
Author(s) -
Bram Yaron,
Lampel Ayala,
ShaltielKaryo Ronit,
Ezer Anat,
ScherzerAttali Roni,
Segal Daniel,
Gazit Ehud
Publication year - 2015
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.201408744
Subject(s) - amyloid (mycology) , islet , chemistry , thioflavin , bimolecular fluorescence complementation , fluorescence , protein aggregation , biochemistry , amyloid disease , biophysics , amyloid fibril , amyloid β , biology , insulin , alzheimer's disease , medicine , pathology , gene , endocrinology , inorganic chemistry , physics , disease , quantum mechanics
Abstract Amyloid deposits are pathological hallmark of a large group of human degenerative disorders of unrelated etiologies. While accumulating evidence suggests that early oligomers may account for tissue degeneration, most detection tools do not allow the monitoring of early association events. Here we exploit bimolecular fluorescence complementation analysis to detect and quantify the dimerization of three major amyloidogenic polypeptides; islet amyloid polypeptide, β‐amyloid and α‐synuclein. The constructed systems provided direct visualization of protein‐protein interactions in which only assembled dimers display strong fluorescent signal. Potential inhibitors that interfere with the initial intermolecular interactions of islet amyloid polypeptide were further identified using this system. Moreover, the identified compounds were able to inhibit the aggregation and cytotoxicity of islet amyloid polypeptide, demonstrating the importance of targeting amyloid dimer formation for future drug development.