Protein phosphatase

Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals.

In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function.

However, dephosphorylation releases phosphates into solution as free ions, because attaching them back to ATP would require energy input.

Unlike most PPPs, PP2C exists in only one subunit but, like PTPs, it displays a wide variety of structural domains that confer unique functions.

They contain the well-known classical receptor (a) and non-receptor PTPs (b), which are strictly tyrosine-specific, and the DSPs (c) which target Ser/Thr as well as Tyr and are the most diverse in terms of substrate specificity.

The haloacid dehalogenase (HAD) superfamily is a further PP group that uses Asp as a nucleophile and was recently shown to have dual-specificity.

The combination of these two functions in Eya reveals a greater complexity of transcriptional gene control than previously thought .

These processes depend on the highly regulated and opposing actions of PKs and PPs, through changes in the phosphorylation of key proteins.

Histone phosphorylation, along with methylation, ubiquitination, sumoylation and acetylation, also regulates access to DNA through chromatin reorganisation.

Furthermore, a wide range of specific inhibitors and targeting partners such as scaffolding, anchoring, and adaptor proteins also contribute to the control of PKs and PPs and recruit them into signalling complexes in neuronal cells.

In neuronal cells, PPs are present in multiple cellular compartments and play a critical role at both pre- and post-synapses, in the cytoplasm and in the nucleus where they regulate gene expression.

As a result, glycogen synthesis is increased and glycogenolysis is decreased, and the net effect is for energy to enter and be stored inside the cell.

Dysregulation of their activity has been linked to several disorders including cognitive ageing and neurodegeneration, as well as cancer, diabetes and obesity.