Amyloidogenicity of naturally occurring full‐length animal IAPP variants

Abstract

The aggregation of the 37-amino acid polypeptide human islet amyloid polypeptide (hIAPP), as either insoluble amyloid or as small oligomers, appears to play a direct role in the death of human pancreatic β-islet cells in type 2 diabetes. hIAPP is considered to be one of the most amyloidogenic proteins known. The quick aggregation of hIAPP leads to the formation of toxic species, such as oligomers and fibers, that damage mammalian cells (both human and rat pancreatic cells). Whether this toxicity is necessary for the progression of type 2 diabetes or merely a side effect of the disease remains unclear. If hIAPP aggregation into toxic amyloid is on-path for developing type 2 diabetes in humans, islet amyloid polypeptide (IAPP) aggregation would likely need to play a similar role within other organisms known to develop the disease. In this work, we compared the aggregation potential and cellular toxicity of full-length IAPP from several diabetic and nondiabetic organisms whose aggregation propensities had not yet been determined for full-length IAPP.

The Role of Glycation on the Aggregation Properties of IAPP

“…The mature 37-residue peptide requires further processing and post-translational modifications such as amidation of the C-terminus and formation of an intramolecular disulfide bridge between Cys2 and Cys7. Mature IAPP is widely regarded as a natively unstructured protein (Jaikaran and Clark, 2001;Padrick and Miranker, 2001) highly prone to aggregation and formation of insoluble cytotoxic amyloid aggregates and fibrils (Lorenzo et al, 1994;Beck Erlach et al, 2019;Chaari and Ladjimi, 2019;Godin et al, 2019;Palato et al, 2019). Independent evidence has pointed to the region between His18 and Asn21 as critical in the in vitro self-assembly of the peptide (Godin et al, 2019;Akter et al, 2020;Ridgway et al, 2020).…”

Recent Advances in the Discovery of Therapeutics to Curtail Islet Amyloid Polypeptide Aggregation for Type 2 Diabetes Treatment

“…[ 22 ] Animals susceptible to amyloid formation and resultant diabetes include nonhuman primates, cats, tigers, lions, lynxes, raccoons, and cougars, while dogs, wolves, and rodents do not form pancreatic amyloid or exhibit diabetes mellitus. [ 23 ] The non‐amyloidogenic properties of organisms unable to misfold and aggregate IAPP can be attributed to variations in the amino acid sequences of their polypeptide structures. [ 24 ] It has been shown that the 20–29 residues of the IAPP 37‐amino acid chain have a significant effect on the amyloidogenicity.…”

Linking hIAPP misfolding and aggregation with type 2 diabetes mellitus: a structural perspective

“…In summary, from the studies summarised in Supplementary Tables S1 and S2, various mutations in the SRE conserved region [ 20–29 ] of IAPP abolish amyloid formation, suggesting these residues as being important in amyloid formation and T2DM progression. Some species that do not show amyloid formation include dog, rat, mouse, guinea pig, degu, and cow [ 152 ]. Although all IAPP sequences from these species carry a S29P substitution, so does the IAPP for cat, which is also amyloidogenic.…”