Programming conformational cooperativity to regulate allosteric protein-oligonucleotide signal transduction

Yuan Liang, Yunkai Qie, Jing Yang, Ranfeng Wu, Shuang Cui, Yuliang Zhao, Greg J. Anderson, Guangjun Nie, Suping Li () and Cheng Zhang ()
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Yuan Liang: Peking University
Yunkai Qie: National Center for Nanoscience and Technology
Jing Yang: North China Electric Power University
Ranfeng Wu: Peking University
Shuang Cui: Peking University
Yuliang Zhao: National Center for Nanoscience and Technology
Greg J. Anderson: Royal Brisbane Hospital
Guangjun Nie: National Center for Nanoscience and Technology
Suping Li: National Center for Nanoscience and Technology
Cheng Zhang: Peking University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract Conformational cooperativity is a universal molecular effect mechanism and plays a critical role in signaling pathways. However, it remains a challenge to develop artificial molecular networks regulated by conformational cooperativity, due to the difficulties in programming and controlling multiple structural interactions. Herein, we develop a cooperative strategy by programming multiple conformational signals, rather than chemical signals, to regulate protein-oligonucleotide signal transduction, taking advantage of the programmability of allosteric DNA constructs. We generate a cooperative regulation mechanism, by which increasing the loop lengths at two different structural modules induced the opposite effects manifesting as down- and up-regulation. We implement allosteric logic operations by using two different proteins. Further, in cell culture we demonstrate the feasibility of this strategy to cooperatively regulate gene expression of PLK1 to inhibit tumor cell proliferation, responding to orthogonal protein-signal stimulation. This programmable conformational cooperativity paradigm has potential applications in the related fields.

Date: 2023
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DOI: 10.1038/s41467-023-40589-z

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