sw ApoMb Amyloid Aggregation under Nondenaturing Conditions: The Role of Native Structure Stability

非变性条件下的 sw ApoMb 淀粉样蛋白聚集:天然结构稳定性的作用

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作者:Natalya S Katina, Vitalii A Balobanov, Nelly B Ilyina, Victor D Vasiliev, Victor V Marchenkov, Anatoly S Glukhov, Alexey D Nikulin, Valentina E Bychkova

Abstract

Investigation of the molecular mechanisms underlying amyloid-related human diseases attracts close attention. These diseases, the number of which currently is above 40, are characterized by formation of peptide or protein aggregates containing a cross-β structure. Most of the amyloidogenesis mechanisms described so far are based on experimental studies of aggregation of short peptides, intrinsically disordered proteins, or proteins under denaturing conditions, and studies of amyloid aggregate formations by structured globular proteins under conditions close to physiological ones are still in the initial stage. We investigated the effect of amino acid substitutions on propensity of the completely helical protein sperm whale apomyoglobin (sw ApoMb) for amyloid formation from its structured state in the absence of denaturing agents. Stability and aggregation of mutated sw ApoMb were studied using circular dichroism, Fourier transform infrared spectroscopy, x-ray diffraction, native electrophoresis, and electron microscopy techniques. Here, we demonstrate that stability of the protein native state determines both protein aggregation propensity and structural peculiarities of formed aggregates. Specifically, structurally stable mutants show low aggregation propensity and moderately destabilized sw ApoMb variants form amyloids, whereas their strongly destabilized mutants form both amyloids and nonamyloid aggregates.

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