Molecular basis for insulin fibril assembly.

Publication Type:

Journal Article

Authors:

Ivanova, Magdalena I; Sievers, Stuart A; Sawaya, Michael R; Wall, Joseph S; Eisenberg, David

Source:

Proc Natl Acad Sci U S A, Volume 106, Issue 45, p.18990-5 (2009)

Keywords:

Amino Acid Sequence, Amyloid, Amyloidosis, Computer Simulation, Crystallography, X-Ray, Insulin, Microscopy, Electron, Models, Molecular, Molecular Sequence Data, Peptide Fragments

Abstract:

<p>In the rare medical condition termed injection amyloidosis, extracellular fibrils of insulin are observed. We found that the segment of the insulin B-chain with sequence LVEALYL is the smallest segment that both nucleates and inhibits the fibrillation of full-length insulin in a molar ratio-dependent manner, suggesting that this segment is central to the cross-beta spine of the insulin fibril. In isolation from the rest of the protein, LVEALYL forms microcrystalline aggregates with fibrillar morphology, the structure of which we determined to 1 A resolution. The LVEALYL segments are stacked into pairs of tightly interdigitated beta-sheets, each pair displaying the dry steric zipper interface typical of amyloid-like fibrils. This structure leads to a model for fibrils of human insulin consistent with electron microscopic, x-ray fiber diffraction, and biochemical studies.</p>