A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily.

A redox-active switch in fructosamine-3-kinases expands the regulatory repertoire of the protein kinase superfamily. Sci Signal. 2020 Jul 07;13(639): Authors: Shrestha S, Katiyar S, Sanz-Rodriguez CE, Kemppinen NR, Kim HW, Kadirvelraj R, Panagos C, Keyhaninejad N, Colonna M, Chopra P, Byrne DP, Boons GJ, van der Knaap E, Eyers PA, Edison AS, Wood ZA, Kannan N Abstract Aberrant regulation of metabolic kinases by altered redox homeostasis substantially contributes to aging and various diseases, such as diabetes. We found that the catalytic activity of a conserved family of fructosamine-3-kinases (FN3Ks), which are evolutionarily related to eukaryotic protein kinases, is regulated by redox-sensitive cysteine residues in the kinase domain. The crystal structure of the FN3K homolog from Arabidopsis thaliana revealed that it forms an unexpected strand-exchange dimer in which the ATP-binding P-loop and adjoining β strands are swapped between two chains in the dimer. This dimeric configuration is characterized by strained interchain disulfide bonds that stabilize the P-loop in an extended conformation. Mutational analysis and solution studies confirmed that the strained disulfides function as redox "switches" to reversibly regulate the activity and dimerization of FN3K. Human FN3K, which contains an equivalent P-loop Cys, was also redox sensitive, whereas ancestral bacterial FN3K homologs, which lack a P-loop Cys, were not. Furthermore, CRI...
Source: Science Signaling - Category: Biomedical Science Authors: Tags: Sci Signal Source Type: research