Sequence divergence in a specific region of islet amyloid polypeptide (IAPP) explains differences in islet amyloid formation between species

Abstract

Amyloid deposits in the islets of Langerhans occur in association with type 2 diabetes mellitus (DM) in humans and cats and consist of a 37-amino-acid polypeptide known as islet amyloid polypeptide (IAPP). In order to find an explanation for the situation that islet amyloid (IA) does not develop in common rodent species, we have deduced the amino acid sequence of the IAPP molecule in mouse, rat and hamster. We find that a specific region of the molecule diverges to a high degree. Synthetic peptides corresponding to this region of human and hamster IAPP were compared for their ability to form amyloid fibrils in vitro. Whereas the human peptide readily formed fibrils with amyloid character, the hamster peptide completely lacked this property. We suggest this to be a likely explanation for the differences in IA formation between humans and rodents and discuss our findings in relation to the type 2 DM syndrome.

Mechanism of IAPP amyloid fibril formation involves an intermediate with a transient β-sheet

“…2B). Two macrocycles have sequences that overlap the N-terminal β-sheet of the fibrils (Mac [11][12][13][14][15][16][17] and Mac [15][16][17][18][19][20][21] ), two overlap the C-terminal sheet (Mac [26][27][28][29][30][31][32] and Mac [31][32][33][34][35][36][37], and one targets the FGAIL region under investigation (Mac [21][22][23][24][25][26][27] ). The sequences of the macrocycles are given in Fig.…”

“…3. Conformational free energy map for the dimerization of hIAPP in terms of order parameters Q [8][9][10][11][12][13][14][15][16] and Q [27][28][29][30][31][32][33][34][35] . Contour lines are drawn every 2.5 kJ/mol.…”

“…Early work revealed a correlation between the ability to form amyloid in vitro and the sequence in the 20-29 region (13,14). The fragment hIAPP [20][21][22][23][24][25][26][27][28][29] (SNNFGAILSS) readily forms amyloid fibrils, as do smaller fragments such as hIAPP [23][24][25][26][27] (13)(14)(15)(16)(17) and hIAPP [21][22][23][24][25][26][27] ; the latter has been characterized with X-ray crystallography (5). Molecular dynamics simulations corroborate the assembly of such fragments into β-sheet structures (18)(19)(20).…”

Human Islet Amyloid Polypeptide Oligomers Disrupt Cell Coupling, Induce Apoptosis, and Impair Insulin Secretion in Isolated Human Islets

“…Islet amyloid has also been reported in recently transplanted human islets (20,21). Human IAPP (h-IAPP) spontaneously aggregates into oligomers and then amyloid fibrils in an aqueous solution, while IAPP from rodents (r-IAPP) does not form oligomers or amyloid but remains in a monomeric form in an aqueous environment (22)(23)(24)(25)(26). Neither the mechanisms that prevent h-IAPP oligomerization in health nor those that allow formation of islet amyloid in type 2 diabetes and recently transplanted islets are known.…”

Altered immunoreactivity of islet amyloid polypeptide (IAPP) may reflect major modifications of the IAPP molecule in amyloidogenesis

“…The sequence differences between the two peptides are mainly located in the central part of the molecules and there is a 10 amino acid segment (positions 20-29) which in humans is completely different from other species. However, the interspecies differences that exist in the IAPP amino acid sequence are also mainly located in the 20-29 segment [5][6][7].Many groups have made antibodies to human or rat IAPP. The immunogen has been either full-length IAPP or segments of the molecule.…”