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Molecular basis for insulin fibril assembly.


ABSTRACT: 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.

SUBMITTER: Ivanova MI 

PROVIDER: S-EPMC2776439 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Molecular basis for insulin fibril assembly.

Ivanova Magdalena I MI   Sievers Stuart A SA   Sawaya Michael R MR   Wall Joseph S JS   Eisenberg David D  

Proceedings of the National Academy of Sciences of the United States of America 20091028 45


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 mor  ...[more]

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