Amyloid fibril structure of islet amyloid polypeptide by cryo-electron microscopy reveals similarities with amyloid beta

Abstract

A critical role of the hormone islet amyloid polypeptide (IAPP) is vividly discussed for Type 2 Diabetes (T2D), where amyloid deposits in pancreatic islets consisting of fibrillar IAPP have been associated with beta cell loss. Here, we applied cryo-electron microscopy to elucidate the structure of IAPP fibrils prepared at physiological pH and reconstructed densities of three dominant polymorphs. An atomic model of the main polymorph comprising residues 13 -37 in a density map of 4.2 Å resolution reveals two S-shaped, intertwined protofilaments. The segment 21-NNFGAIL-27, which is essential for IAPP amyloidogenicity, forms the protofilament interface together with tyrosine 37 and the amidated C-terminus. The main IAPP fibril polymorph resembles polymorphs of the Alzheimer disease (AD)-associated amyloid-β peptide (Aβ), which is striking in light of the epidemiological link between T2D and AD and reports on IAPP-Aβ cross-seeding in vivo. The results structurally link the early-onset T2D IAPP genetic polymorphism S20G with the early-onset AD Arctic mutation E22G of Aβ, rationalize previous data on IAPP fibrils, help to elucidate mechanisms of amyloid formation and toxicity, and support the design of fibril growth inhibitors as well as imaging probes for early detection of IAPP fibrils.

A Different hIAPP Polymorph Is Observed in Human Serum Than in Aqueous Buffer: Demonstration of a New Method for Studying Amyloid Fibril Structure Using Infrared Spectroscopy

“…This fibril structure is characterized by increased coupling strength in the G24/A25 residues, consistent with well-ordered parallel stacking of strands. The 2D IR spectra appear to be consistent with a recently published cryoEM polymorph in which these residues form the amyloidogenic core of the fibrils, which is a region of particular interest for hIAPP. The fact that different structures are observed in serum than in buffer highlights the importance of studying aggregation under as-close-to-possible biologically relevant conditions, which this new infrared method enables.…”

“…Our results in serum indicate that the FGAIL region G24A25 residues may adopt a β-sheet in the fibril formed under biological conditions. Indeed, a new hIAPP polymorph was recently reported using cryoEM at pH 6 in which G24 and A25 form the hydrophobic core of the fibrils . That structure would be consistent with the large and negative coupling constants measured in the 2D IR experiments.…”

Cryo-EM structure and inhibitor design of human IAPP (amylin) fibrils

“…We also observed ribbons in our samples, but those are not amenable to cryo-EM analysis. In addition, Röder et al have recently reported the structure of an hIAPP polymorph called PM1, featuring two S-shaped protofilaments with zipper-like interfaces at the sequence 21 NNFGAIL 27 , but with a different fold than ours 55 . We note that pathogenic amyloid fibrils are usually polymorphic and all these models may therefore represent different biologically relevant polymorphs of hIAPP.…”

“…For example, paired helical filaments and straight filaments of tau are both observed in Alzheimer’s disease patients 29 . A notable distinction is that Röder et al used peptides with amidated C-terminus, which forms a weak hydrogen bond with the Asn21 side chain 55 . Thus, C-terminal amidation of hIAPP may favor the PM1 polymorph, whereas a free carboxylate would not be able to participate in an analogous bond unless protonated.…”

Site-Specific Alkylation of the Islet Amyloid Polypeptide Accelerates Self-Assembly and Potentiates Perturbation of Lipid Membranes

“…76 According to the models of IAPP fibrils inferred from solidstate NMR (hairpin conformation) and, more recently, from cryo-EM (S-shaped conformation), the His-18 side chain projects outward from the protofilament, likely participating in packing into mature fibrils. 48,77,78 Studies have revealed that His-18 interacts with Thr-36, or Tyr-37, from the opposite protofilament. 79,80 Alternatively, molecular dynamics simulation based on the solid-state NMR model of Tycko has proposed that His-18 forms an interlayer hydrogen bond with Ser-19 of the adjacent monomer within the same protofilament, contributing to elongation.…”