Autophosphorylation

Autophosphorylation is the process by which a protein kinase catalyzes the transfer of a phosphate group from ATP to a residue within itself, typically on serine, threonine, or tyrosine. This self-modification can regulate the enzyme’s catalytic activity, alter its conformation, and affect interactions with other proteins, thereby modulating signal transduction and cellular processes.

Mechanistically, autophosphorylation can occur in cis, where the kinase phosphorylates a residue on the same molecule, or in trans, where one molecule in a dimer phosphorylates a partner molecule. In many receptor and non-receptor tyrosine kinases, ligand-induced dimerization promotes trans-autophosphorylation of activation loops and additional sites, increasing kinase activity and generating phosphotyrosine motifs that recruit downstream signaling proteins. Serine/threonine kinases also undergo autophosphorylation, often to regulate activity or substrate recognition.

Examples include receptor tyrosine kinases such as the epidermal growth factor receptor (EGFR), whose autophosphorylation after ligand binding creates docking sites for signaling adaptors; and Src family kinases, where autophosphorylation of specific tyrosines contributes to regulatory control. Autophosphorylation is also observed in various serine/threonine kinases and in bacterial histidine kinases, which autophosphorylate on a histidine residue using ATP as part of a two-component signaling system that transfers the phosphate to a response regulator.

Biological significance of autophosphorylation lies in its role as a rapid and reversible regulatory mechanism, enabling enzymes to respond to stimuli, propagate signals, and coordinate complex cellular responses.