Atomic resolution structure of full-length human insulin fibrils

Area of Science:

• Biophysics
• Structural Biology
• Diabetology

Background:

• Insulin-dependent diabetes mellitus patients develop insulin amyloidosis at injection sites.
• Insulin fibrils, primarily composed of full-length insulin, are implicated in this condition.
• Previous studies lacked atomic-level detail on insulin fibril architecture.

Purpose of the Study:

• To determine the atomic resolution structure of a monomorphic insulin amyloid fibril.
• To elucidate the structural basis of insulin aggregation and amyloid formation.
• To provide a foundation for developing therapeutic strategies against insulin amyloidosis.

Main Methods:

• Magic angle spinning solid-state Nuclear Magnetic Resonance (NMR) spectroscopy.
• Atomic resolution structural determination of insulin amyloid fibrils.

Main Results:

• The atomic structure of the insulin monomer revealed a U-shaped fold with chains A and B arranged parallel and perpendicular to the fibril axis.
• Each insulin chain consists of two beta-strands.
• Two hydrophobic clusters and three disulfide bridges define the amyloid core.
• A hydrophobic surface on the monomer suggests a dimerization and oligomerization interface.

Conclusions:

• The determined structure provides critical insights into insulin fibril assembly.
• This atomic-level information can guide the development of drugs targeting fibril surfaces.
• Therapeutic strategies can be devised to disrupt secondary nucleation and mitigate insulin aggregation.