Figure 1.
The four IAPP variants listed with aggregation propensities (Na4vSS values from AGGRESCAN server).
The residues that differ from those of hIAPP are mainly located between residues 4–31 (see residues in red in the sequences). While human and cat IAPP has strong aggregation tendency contributing to T2D, rat and pig IAPP doesn't aggregate under normal conditions and is not toxic to β-cells.
Figure 2.
Two opposite roles of hIAPP in T2D.
In T2D, over-nutrition and inactivity lead to a high demand for pancreatic β-cells to produce insulin and hIAPP, two hormones that play a critical role in lowering blood glucose. Whereas correctly folded insulin and hIAPP function to reduce blood glucose (left loop), the misfolded form of hIAPP is amyloidogenic and toxic to the β-cells (right loop). +: increase −: decrease.
Figure 3.
Secondary structure propensities of the four IAPP variants at 300 K.
Stardard deviation was calculated from the last 3 blocks of the simulation data (100 ns of each) at 300 K.
Figure 4.
Position-dependent secondary structure propensities for the four IAPP variants from the last 300 ns at 300 K.
Figure 5.
Representative structures of super structural families for each IAPP variant.
Standard deviation was calculated from the last 3 blocks of the simulation data (100 ns of each) at 300 K (See Figures S2 for all structural families in each super family from the last block). The backbone is shown in cartoon and the secondary structure is coded by color: coil in silver, β-sheet in yellow, isolated β-bridge in tan and turn in cyan. The N-terminus is indicated by a red ball.
Table 1.
Solvation energy of the super structural families of the four IAPP variants (Fig. 5).
Figure 6.
Root mean square fluctuation (RMSF) of each residue (Cα atom) of the four IAPP variants in the super structural families at 300 K.
Residues 1–17 were aligned preceding the RMSF calculations.
Table 2.
Diminished amount of putative helix-coil hormone-competent conformation in hIAPP relative to rIAPP seen in simulation, and its link to diminished normal hormone function of hIAPP relative to rIAPP.
Figure 7.
Schematic representation of misfolding/aggregation mechanism of hIAPP.
Left: Helix-coil structure for normal function; Middle: aggregation-prone β-rich monomers; Right: early putative toxic dimers (Dupuis et al. JACS 2011). The question mark indicates the hairpins may further form cylindrin-like toxic oligomers, modeled from the cylindrical barrel of an amyloid peptide (PDB id: 3SGR) (Laganowsky et al. Science 2012). The isomerization symbol indicates that at some, as yet unknown size, the β-strand aggregates must rearrange to the β-sheet aggregates found in the fibrils. N-terminus is indicated by red ball, residues 23–29 in the “mutation region” are in red. In the β-hairpin, residues 19S-20S-21N-22N form a turn and residues 11–19 and 23–33 form two β-strands.