Structural basis for allosteric regulation of human phosphofructokinase-1

Eric M. Lynch, Heather Hansen, Lauren Salay, Madison Cooper, Stepan Timr, Justin M. Kollman () and Bradley A. Webb ()
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Eric M. Lynch: University of Washington
Heather Hansen: West Virginia University
Lauren Salay: University of Washington
Madison Cooper: West Virginia University
Stepan Timr: Czech Academy of Sciences
Justin M. Kollman: University of Washington
Bradley A. Webb: West Virginia University

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Phosphofructokinase-1 (PFK1) catalyzes the rate-limiting step of glycolysis, committing glucose to conversion into cellular energy. PFK1 is highly regulated to respond to the changing energy needs of the cell. In bacteria, the structural basis of PFK1 regulation is a textbook example of allostery; molecular signals of low and high cellular energy promote transition between an active R-state and inactive T-state conformation, respectively. Little is known, however, about the structural basis for regulation of eukaryotic PFK1. Here, we determine structures of the human liver isoform of PFK1 (PFKL) in the R- and T-state by cryoEM, providing insight into eukaryotic PFK1 allosteric regulatory mechanisms. The T-state structure reveals conformational differences between the bacterial and eukaryotic enzyme, the mechanisms of allosteric inhibition by ATP binding at multiple sites, and an autoinhibitory role of the C-terminus in stabilizing the T-state. We also determine structures of PFKL filaments that define the mechanism of higher-order assembly and demonstrate that these structures are necessary for higher-order assembly of PFKL in cells.

Date: 2024
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DOI: 10.1038/s41467-024-51808-6

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