Dataset Information

Beta-2-microglobulin fibrils with multiple polymorphs formed at pH 2

ABSTRACT:

SUBMITTER: Matthew Gregory Iadanza

PROVIDER: EMPIAR-10207 | biostudies-other |

REPOSITORIES: biostudies-other

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Publications

The structure of a β2-microglobulin fibril suggests a molecular basis for its amyloid polymorphism.

Iadanza Matthew G MG Silvers Robert R Boardman Joshua J Smith Hugh I HI Karamanos Theodoros K TK Debelouchina Galia T GT Su Yongchao Y Griffin Robert G RG Ranson Neil A NA Radford Sheena E SE

Nature communications 20181030 1

All amyloid fibrils contain a cross-β fold. How this structure differs in fibrils formed from proteins associated with different diseases remains unclear. Here, we combine cryo-EM and MAS-NMR to determine the structure of an amyloid fibril formed in vitro from β2-microglobulin (β2m), the culprit protein of dialysis-related amyloidosis. The fibril is composed of two identical protofilaments assembled from subunits that do not share β2m's native tertiary fold, but ...[more]

PMID: 30375379

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Project description:The persistence of high concentrations of beta-2-microglobulin (?2M) in the blood of patients with acute renal failure leads to the development of the dialysis-related amyloidosis. This disease manifests in the deposition of amyloid fibrils formed from the various forms of ?2M in the tissues and biological fluids of patients. In this paper, the amyloid fibrils formed from the full-length ?2M (?2m) and its variants that lack the 6 and 10 N-terminal amino acids of the protein polypeptide chain (?N6?2m and ?N10?2m, respectively) were probed by using the fluorescent dye thioflavin T (ThT). For this aim, the tested solutions were prepared via the equilibrium microdialysis approach. Spectroscopic analysis of the obtained samples allowed us to detect one binding mode (type) of ThT interaction with all the studied variants of ?2M amyloid fibrils with affinity ~10? M-1. This interaction can be explained by the dye molecules incorporation into the grooves that were formed by the amino acids side chains of amyloid protofibrils along the long axis of the fibrils. The decrease in the affinity and stoichiometry of the dye interaction with ?2M fibrils, as well as in the fluorescence quantum yield and lifetime of the bound dye upon the shortening of the protein amino acid sequence were shown. The observed differences in the ThT-?2M fibrils binding parameters and characteristics of the bound dye allowed to prove not only the difference of the ?N10?2m fibrils from other ?2M fibrils (that can be detected visually, for example, by transmission electron microscopy (TEM), but also the differences between ?2m and ?N6?2m fibrils (that can not be unequivocally confirmed by other approaches). These results prove an essential role of N-terminal amino acids of the protein in the formation of the ?2M amyloid fibrils. Information about amyloidogenic protein sequences can be claimed in the development of ways to inhibit ?2M fibrillogenesis for the treatment of dialysis-related amyloidosis.

Dataset Information

Beta-2-microglobulin fibrils with multiple polymorphs formed at pH 2

Publications

The structure of a β<sub>2</sub>-microglobulin fibril suggests a molecular basis for its amyloid polymorphism.

Similar Datasets

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