Allosteric Regulation of Human Phosphofructokinase-1 Through Symmetry Reorganization of Protein Contact Networks

Phosphofructokinase-1 (PFK1) is a key regulatory enzyme of glycolysis, controlling the irreversible conversion of fructose-6-phosphate to fructose-1,6-bisphosphate. Its activity is finely tuned by allosteric effectors such as ATP, ADP, and fructose-2,6-bisphosphate. In this study, starting from recently resolved cryo-EM structures of the human liver isoform of PFK1 in both its active (R) and inactive (T) states, we analyze the residue-level interactions adopting a network-based approach (Protein Contact Network). We demonstrate that the two states exhibit distinct inter-subunit communication patterns, participation coefficients, betweenness centrality and symmetry. These features suggest a reorganization of inter-subunit communication between the R and T states, characterized by a transition from localized, bottleneck-dominated communication in the T state to a more distributed and symmetric network in the R state. Our findings offer new insight into the structural logic underlying allosteric control in homo-tetrameric metabolic enzymes.