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Structural Insight into IAPP‐Derived Amyloid Inhibitors and Their Mechanism of Action
Author(s) -
Niu Zheng,
Prade Elke,
Malideli Eleni,
Hille Kathleen,
Jussupow Alexander,
Mideksa Yonatan G.,
Yan LiMei,
Qian Chen,
Fleisch Markus,
Messias Ana C.,
Sarkar Riddhiman,
Sattler Michael,
Lamb Don C.,
Feige Matthias J.,
Camilloni Carlo,
Kapurniotu Aphrodite,
Reif Bernd
Publication year - 2020
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.201914559
Subject(s) - chemistry , amyloid (mycology) , biophysics , peptide , molecular dynamics , function (biology) , dynamic light scattering , colloid , nanotechnology , biochemistry , nanoparticle , materials science , computational chemistry , biology , organic chemistry , microbiology and biotechnology , inorganic chemistry
Designed peptides derived from the islet amyloid polypeptide (IAPP) cross‐amyloid interaction surface with Aβ (termed interaction surface mimics or ISMs) have been shown to be highly potent inhibitors of Aβ amyloid self‐assembly. However, the molecular mechanism of their function is not well understood. Using solution‐state and solid‐state NMR spectroscopy in combination with ensemble‐averaged dynamics simulations and other biophysical methods including TEM, fluorescence spectroscopy and microscopy, and DLS, we characterize ISM structural preferences and interactions. We find that the ISM peptide R3‐GI is highly dynamic, can adopt a β‐like structure, and oligomerizes into colloid‐like assemblies in a process that is reminiscent of liquid–liquid phase separation (LLPS). Our results suggest that such assemblies yield multivalent surfaces for interactions with Aβ40. Sequestration of substrates into these colloid‐like structures provides a mechanistic basis for ISM function and the design of novel potent anti‐amyloid molecules.