Protein Kinases and Phosphatases

Abstract

Reversible protein phosphorylation is the most prominent posttranslational regulatory mechanism in eukaryotes. Protein kinases catalyze the addition of a phosphoester group to proteins while protein phosphatases oppose kinase activity by removing phosphates. The recent sequencing of numerous genomes has allowed for the identification and classification of most if not all kinases and phosphatases. Kinases represent a large group of enzymes (>500 in humans) and are classified by sequence similarity, with most kinases containing a conserved catalytic domain. Phosphatases are a smaller group (∼140 in humans) and are classified by their catalytic mechanisms, as well as sequence similarity. Most kinases and phosphatases contain domains involved in intramolecular regulation of the catalytic domain. In contrast, some of the abundant Ser/Thr phosphatases form holoenzymes with a variety of regulatory subunits, which affect both localization and substrate binding.

Precise regulation of cellular responses requires the formation of large signaling complexes containing both kinases and phosphatases. In neurons, regulatory complexes containing ion channels and neurotransmitter receptors are important for basal neurotransmission and synaptic plasticity. Such microcompart-mentalization of kinases and phosphatases allows for synapse-specific adjustments of synaptic strength. Recent advances in proteomics techniques have led to the identification of synaptic protein-protein interaction and phosphorylation networks, which provide a first global picture of the molecular machinery that underlies neuronal communication.