Investigating the trade-off between folding and function in a multidomain Y-family DNA polymerase

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Abstract

The way in which multidomain proteins fold has been a puzzling question for decades. Until now, the mechanisms and functions of domain interactions involved in multidomain protein folding have been obscure. Here, we develop structure-based models to investigate the folding and DNA-binding processes of the multidomain Y-family DNA polymerase IV (DPO4). We uncover shifts in folding mechanism among ordered domain-wise folding, backtracking folding, and cooperative folding, modulated by interdomain interactions. These lead to "U-shaped' folding kinetics. We characterize the effects of interdomain flexibility on the promotion of DPO4-DNA (un)binding, which probably contributes to the ability of DPO4 to bypass DNA lesions, a known biological role of Y-family polymerases. We suggest that the native topology of DPO4 leads to a trade-off between fast, stable folding and tight functional DNA binding. Our approach provides an effective way to quantitatively correlate the roles of protein interactions in conformational dynamics at the multidomain level.

Data availability

The necessary files for setting up Gromacs (version 4.5.7 with PLUMED version 2.5.0) simulations and analysis programs/scripts are publicly available at https://osf.io/qu5ve/.

The following data sets were generated

1. Chu X
(2020) Folding and Binding of DPO4
OSF, qu5ve.

https://osf.io/qu5ve/

Article and author information

Author details

Xiakun Chu

Chemistry, Stony Brook University, Stony Brook, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3166-7070
Zucai Suo

Department of Biomedical Sciences, Florida State University, Tallahassee, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-3871-3420
Jin Wang

Chemistry, Stony Brook University, Stony Brook, United States

For correspondence
jin.wang.1@stonybrook.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-2841-4913

Funding

National Institute of General Medical Sciences (R01GM124177)

Zucai Suo
Jin Wang

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.