Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers
Author
Dasari, Anvesh K. R.; Hughes, Robert M.; Wi, Sungsool; Hung, Ivan; Gan, Zhehong; Kelly, Jeffrey W.; Lim, Kwang Hun
Abstract
Characterization of small oligomers formed at an early stage of amyloid formation is critical to
understanding molecular mechanism of pathogenic aggregation process. Here we identifed and
characterized cytotoxic oligomeric intermediates populated during transthyretin (TTR) aggregation
process. Under the amyloid-forming conditions, TTR initially forms a dimer through interactions
between outer strands. The dimers are then associated to form a hexamer with a spherical shape, which
serves as a building block to self-assemble into cytotoxic oligomers. Notably, wild-type (WT) TTR tends
to form linear oligomers, while aTTR variant(G53A) prefers forming annular oligomers with pore-like
structures. Structural analyses of the amyloidogenic intermediates using circular dichroism (CD) and
solid-state NMR revealthatthe dimer and oligomers have a signifcant degree of native-like β-sheet
structures (35–38%), but with more disordered regions (~60%)than those of nativeTTR.TheTTR variant
oligomers are also less structured than WT oligomers. The partially folded nature of the oligomeric
intermediates might be a common structural property of cytotoxic oligomers.The higher fexibility of
the dimer and oligomers may also compensate for the entropic loss due to the oligomerization of the
monomers.
Date
2019-01-10
Citation:
APA:
Dasari, Anvesh K. R., & Hughes, Robert M., & Wi, Sungsool, & Hung, Ivan, & Gan, Zhehong, & Kelly, Jeffrey W., & Lim, Kwang Hun. (January 2019).
Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers.
,
(),
-
. Retrieved from
http://hdl.handle.net/10342/8343
MLA:
Dasari, Anvesh K. R., and Hughes, Robert M., and Wi, Sungsool, and Hung, Ivan, and Gan, Zhehong, and Kelly, Jeffrey W., and Lim, Kwang Hun.
"Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers". .
. (),
January 2019.
September 21, 2023.
http://hdl.handle.net/10342/8343.
Chicago:
Dasari, Anvesh K. R. and Hughes, Robert M. and Wi, Sungsool and Hung, Ivan and Gan, Zhehong and Kelly, Jeffrey W. and Lim, Kwang Hun,
"Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers," , no.
(January 2019),
http://hdl.handle.net/10342/8343 (accessed
September 21, 2023).
AMA:
Dasari, Anvesh K. R., Hughes, Robert M., Wi, Sungsool, Hung, Ivan, Gan, Zhehong, Kelly, Jeffrey W., Lim, Kwang Hun.
Transthyretin Aggregation Pathway toward the Formation of Distinct Cytotoxic Oligomers. .
January 2019;
():
.
http://hdl.handle.net/10342/8343. Accessed
September 21, 2023.
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