Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Anvesh K. R.,Hughes,Robert M.,Wi,Sungsool,Hung,Ivan,Gan,Z Dasari (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Characterization of small oligomers formed at an early stage of amyloid formation is critical tounderstanding molecular mechanism of pathogenic aggregation process. Here we identifed andcharacterized cytotoxic oligomeric intermediates populated during transthyretin (TTR) aggregationprocess. Under the amyloid-forming conditions, TTR initially forms a dimer through interactionsbetween outer strands. The dimers are then associated to form a hexamer with a spherical shape, whichserves as a building block to self-assemble into cytotoxic oligomers. Notably, wild-type (WT) TTR tendsto form linear oligomers, while aTTR variant(G53A) prefers forming annular oligomers with pore-likestructures. Structural analyses of the amyloidogenic intermediates using circular dichroism (CD) andsolid-state NMR revealthatthe dimer and oligomers have a signifcant degree of native-like β-sheetstructures (35--38%), but with more disordered regions (~60%)than those of nativeTTR.TheTTR variantoligomers are also less structured than WT oligomers. The partially folded nature of the oligomericintermediates might be a common structural property of cytotoxic oligomers.The higher fexibility ofthe dimer and oligomers may also compensate for the entropic loss due to the oligomerization of themonomers.

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Other

Language: English

Date: 2019

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