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- W4386360410 abstract "Abstract Protein folding may involve folding intermediates. Ubiquitin (Ub) is a 76-residue small protein essential in post-translational modification and cell signaling. Ub is also a model system of protein folding. Previous studies have indicated the involvement of a folding intermediate, as Ub C-terminal residues, including strand β5, only dock correctly at a later stage. The natively folded Ub undergoes conformational dynamics over a vast range of timescales. At the millisecond timescale, Ub transiently digresses to a C-terminally retracted state, which is extremely rare and has only been recently identified at an elevated temperature. Herein through a conjoint use of NMR, MS, and MD simulations, we have established a link between Ub millisecond dynamics and protein stability. Among the alanine mutations that have been systematically introduced to the hydrophobic residues in β5, L67A and L69A elevate the population of the retracted state and enhance conformational interconversion, which facilitates the undocking of β5 and the exposure of protein hydrophobic core. Conversely, L71A and L73A mutations decrease the population of the retracted state and quench millisecond dynamics, which causes a significant enhancement of protein stability. As such, the transition state of Ub millisecond dynamics is the much sought-after folding intermediate, whereas C-terminal mutations alleviate the dependence on this intermediate and reduce the unfolding to an all-or-none process. Though having a negative impact on protein stability, Ub millisecond dynamics likely facilitate proper protein turnover and allow the fulfillment of its biological function." @default.
- W4386360410 created "2023-09-02" @default.
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- W4386360410 date "2023-09-01" @default.
- W4386360410 modified "2023-10-16" @default.
- W4386360410 title "Enhancement of Protein Stability by Quenching Millisecond Conformational Dynamics" @default.
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- W4386360410 doi "https://doi.org/10.1101/2023.08.30.555640" @default.
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