Mapping the conformational energy landscape of Abl kinase using ClyA nanopore tweezers

Fanjun Li, Monifa A. Fahie, Kaitlyn M. Gilliam, Ryan Pham and Min Chen ()
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Fanjun Li: University of Massachusetts Amherst
Monifa A. Fahie: University of Massachusetts Amherst
Kaitlyn M. Gilliam: University of Massachusetts Amherst
Ryan Pham: University of Massachusetts Amherst
Min Chen: University of Massachusetts Amherst

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: Abstract Protein kinases play central roles in cellular regulation by catalyzing the phosphorylation of target proteins. Kinases have inherent structural flexibility allowing them to switch between active and inactive states. Quantitative characterization of kinase conformational dynamics is challenging. Here, we use nanopore tweezers to assess the conformational dynamics of Abl kinase domain, which is shown to interconvert between two major conformational states where one conformation comprises three sub-states. Analysis of kinase-substrate and kinase-inhibitor interactions uncovers the functional roles of relevant states and enables the elucidation of the mechanism underlying the catalytic deficiency of an inactive Abl mutant G321V. Furthermore, we obtain the energy landscape of Abl kinase by quantifying the population and transition rates of the conformational states. These results extend the view on the dynamic nature of Abl kinase and suggest nanopore tweezers can be used as an efficient tool for other members of the human kinome.

Date: 2022
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DOI: 10.1038/s41467-022-31215-5

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