The Structure of Human IAPP Fibrils Reflects Membrane and pH Conditions

Area of Science:

• Biophysics
• Structural Biology
• Biochemistry

Background:

• Amyloid aggregation of human islet amyloid polypeptide (hIAPP) is linked to type 2 diabetes and β-cell dysfunction.
• Existing in vitro models often lack physiological relevance, failing to account for membrane interactions and native pH.
• Structural data on ex vivo hIAPP fibrils are scarce, hindering a complete understanding of disease mechanisms.

Purpose of the Study:

• To determine the high-resolution structure of hIAPP fibrils formed under physiologically relevant conditions, specifically involving phospholipid membranes and extracellular pH.
• To investigate the structural plasticity of hIAPP during aggregation in a membrane environment.
• To provide insights into the structural basis of hIAPP-mediated β-cell dysfunction in type 2 diabetes.

Main Methods:

• Solid-state NMR spectroscopy was employed to analyze hIAPP fibrils.
• Fibrils were formed in the presence of phospholipid membranes at extracellular pH (7.4) and intracellular pH (5.3).
• Structural characterization focused on protofilament architecture, N-terminal and C-terminal regions, and overall fold.

Main Results:

• Membrane-mediated hIAPP fibrils formed at pH 7.4 are homogeneous and adopt an L-shaped protofilament architecture with a distinct N-terminal β-strand.
• The fibril core (N14-L27) exhibits the conserved CF1 fold, a β-arch structure also found in nonlipidic fibrils.
• Fibrils formed at intracellular pH (5.3) are structurally heterogeneous with differences in the C-terminus, indicating significant structural plasticity of hIAPP in membrane environments.

Conclusions:

• The study provides the first high-resolution structure of membrane-mediated hIAPP fibrils under physiologically relevant extracellular conditions.
• hIAPP demonstrates substantial structural plasticity, transitioning from helical monomers to β-hairpin oligomers and β-arch-rich fibrils.
• Accurate modeling of amyloid aggregation requires consideration of membrane interactions and native pH to understand disease pathology.