Structural Insight into IAPP‐Derived Amyloid Inhibitors and Their Mechanism of Action

Abstract

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.

Proteostasis of Islet Amyloid Polypeptide: A Molecular Perspective of Risk Factors and Protective Strategies for Type II Diabetes

“…311 Most oligomeric states had larger α-helical than β-sheet content, and in about 5% of the simulations β-barrel conformations were formed by pentamers and hexamers. Furthermore, the same research group reported that five fragments of amyloidogenic peptides, namely the cytotoxic hIAPP (19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and its Ser20Gly mutant as well as hIAPP (22)(23)(24)(25)(26)(27)(28), Aβ (16)(17)(18)(19)(20)(21)(22) and α-nuclein (68)(69)(70)(71)(72)(73)(74)(75)(76)(77)(78), formed oligomers with β-barrel content in DMD simulations while two non-toxic fragments (hIAPP (15)(16)(17)(18)(19)(20)(21)(22)(23)…”

“…333 Niu et al investigated the inhibition of Aβ aggregation by derivatives of IAPP whose design was inspired by the IAPP/Aβ cross-amyloid interaction surface. 334 The authors employed a combined experimental and computational approach based on fluorescence spectroscopy, solutionstate and solid-state NMR spectroscopy, transmission electron microscopy (TEM), dynamic light scattering, and MD simulations. The multi-disciplinary study revealed that a peptide derived from the two segments of IAPP (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18) and IAPP (22)(23)(24)(25)(26)(27)(28) (linked by an -RRR-tripeptide and with methylated backbone nitrogen on the Phe23 and Ala25) is disordered, has transient β-sheet content, and can oligomerize into colloid-like assemblies that can interact with Aβ40.…”

“…Niu et al investigated the inhibition of Aβ aggregation by derivatives of IAPP whose design was inspired by the IAPP/Aβ cross-amyloid interaction surface . The authors employed a combined experimental and computational approach based on fluorescence spectroscopy, solution-state and solid-state NMR spectroscopy, transmission electron microscopy (TEM), dynamic light scattering, and MD simulations.…”

“…The multidisciplinary study revealed that a peptide derived from the two segments of IAPP(8−18) and IAPP(22−28) (linked by an -RRR-tripeptide and with methylated backbone nitrogen on the Phe23 and Ala25) is disordered, has transient β-sheet content, and can oligomerize into colloid-like assemblies that can interact with Aβ40. 334 Baram et al have reported π-π interactions between Tyr16 in insulin and Phe15 in hIAPP by MD simulations of free insulin approaching model structures of hIAPP fibrils. 335 These findings are relevant in vivo because insulin and hIAPP are both secreted by the pancreas and have been observed to form mixed aggregates.…”

Field and magic angle spinning frequency dependence of proton resonances in rotating solids

“…Proton detection has become a popular tool [17][18][19][20] for investigating large biomolecules in recent years, and new strategies ranging from hardware development to isotope labelling have been developed. A wide variety of supramolecular assemblies [21,22] such as amyloid fibrils [23][24][25][26][27][28][29], membrane proteins, ribosomal subunits [30] and viral capsids [31][32][33] have meanwhile been studied with atomic resolution employing proton-detected MAS solid state NMR.…”