Abstract
Protein glycation is a universal, non-enzymatic modification that occurs when a sugar covalently attaches to a primary amine. These spontaneous modifications may have deleterious or regulatory effects on protein function, and their removal is mediated by the conserved metabolic kinase fructosamine-3-kinase (FN3K). Despite its crucial role in protein repair, we currently have a poor understanding of how FN3K engages or phosphorylates its substrates. By integrating structural biology and biochemistry, we elucidated the catalytic mechanism for FN3K-mediated protein deglycation. Our work identifies key amino acids required for binding and phosphorylating glycated substrates and reveals the molecular basis of an evolutionarily conserved protein repair pathway. Additional structural-functional studies revealed unique structural features of human FN3K as well as differences in the dimerization behavior and regulation of FN3K family members. Our findings improve our understanding of the structure of FN3K and its catalytic mechanism, which opens new avenues for therapeutically targeting FN3K.
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