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.
Highlights
Peptides mimicking the cross-amyloid interactions surface of the type 2 diabetes (T2D) human islet amyloid polypeptide with the Alzheimer’s disease β-amyloid protein Aβ40/42, termed Interaction Surface Mimics (ISMs), have been shown to be nanomolar inhibitors of amyloid self-assembly of Aβ40/42.[1]
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 which is reminiscent of liquid-liquid phase separation (LLPS)
The design of the ISMs was based on the finding that amyloids are generally composed of a β-sheet-turn-β-sheet structural motif and that IAPP uses the same two binding regions for both its amyloid self- and its cross-amyloid hetero-assembly with Aβ40/42.[1a, 2] ISMs were derived by linking the two hot segments IAPP(8-18) and IAPP(22-28) in native or N-methylated form to each other via different linkers, mostly tripeptide sequences consisting of identical amino acids; notably, these two segments are highly homologous to segments of the amyloid core of Aβ.[3]
Summary
Peptides mimicking the cross-amyloid interactions surface of the type 2 diabetes (T2D) human islet amyloid polypeptide (hIAPP) with the Alzheimer’s disease β-amyloid protein Aβ40/42, termed Interaction Surface Mimics (ISMs), have been shown to be nanomolar inhibitors of amyloid self-assembly of Aβ40/42.[1]. It has been recognized recently that liquid-liquid phase separation (LLPS) plays an important role for self-organization of membrane-less cellular organelles.[4] In particular, proteins containing low complexity sequences can form protein-rich droplets.[5] Phase separation is the driving force for the formation of membrane-less cellular organelles like nucleoli, stress granules, P-bodies and other cellular compartments.[6] Similar to stress granules, hydrophobic small molecules undergo LLPS, adopt colloidal structures in aqueous environment,[7] and recruit amyloidogenic proteins into its core in which amyloids adopt an altered structure that prevents amyloid neurotoxicity.[8] The elevated local concentration facilitates interactions with the amyloid In this manuscript, we show that R3-GI is highly dynamic, can adopt a β-like structure and oligomerizes into colloid-like assemblies. The suggested mechanism provides a possible mechanistic scenario for the potent amyloid inhibitor function of ISMs
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