Significance of Knotted Structures for Function of Proteins and Nucleic Acids
Thursday Abstracts
Knotted Structures in Refolding and Cotranslational Folding of Multi-domain Protein
Shoji Takada
.
Kyoto, Japan.
Co-translational folding (CTF) is known to facilitate correct folding in vivo, but its precise
mechanism remains elusive. For the CTF of a three-domain protein SufI, it was reported that the
translational attenuation is obligatory to acquire the functional state. Here, for SufI, we
performed comparative molecular simulations that mimic CTF as well as refolding schemes,
addressing how the translational attenuation affects the folding. First, a CTF scheme that relied
on a codon-based prediction of translational rates exhibited folding probability markedly higher
than that by the refolding scheme. When the CTF schedule is speeded up, the success rate
dropped to a probability similar to that by the refolding scheme. Whereas, the CTF that has a
uniformly slow rate led to essentially the same result as the codon-based CTF scheme. Most
notably, misfolding of the middle domain was much more frequent in the refolding scheme than
that in the codon-based CTF scheme. The middle domain is less stable and can fold only when it
is stabilized via interactions with the N-terminal domain. In a kinetic trap, while a segment of the
middle domain entangled with the C-terminal domain, domain-domain interfaces were formed to
lock these interfaces. Thus obtained knotted misfolds could not be escaped in the simulations.
Folding pathway networks showed that the refolding scheme sampled diverse states with no
clear pathways, while the codon-based CTF showed a clear and narrower pathways to the native
state. The degree of folding acquisition was shown to modestly correlate with the elongation
time.
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