Phosphoinositol-specific phospholipase C (PLC; (3.1.4.11) plays an important role in signal transduction processes [1], mediating the cellular actions of a variety of hormones, neurotransmitters and growth factors. Upon agonist-dependent activation, PLC catalyses the hydrolysis of membrane phosphatidylinositol 4,5-bisphosphate (PIP2), generating the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds specific intracellular receptors to trigger Ca²⁺ mobilisation, while DAG mediates activation of a family of protein kinase C isozymes. This catalytic process is tightly regulated by reversible phosphorylation and binding of regulatory proteins [2, 3, 4]. Based on molecular size, immunoreactivity and amino acid sequence, several subtypes have been classified. Overall, sequence identity between sub-types is low, yet all isoforms share two conserved domains, designated X and Y.

All eukaryotic PI-PLCs contain two regions of homology, sometimes referred to as 'X-box' and 'Y-box'. The order of these two regions is always the same (NH2-X-Y-COOH), but the spacing is variable. In most isoforms, the distance between these two regions is only 50-100 residues, for example, in PLC-beta subtypes, X and Y domains are separated by a stretch of 70-120 amino acids rich in Ser, Thr and acidic residues (their C terminus is rich in basic residues). However, in PLC-gammas, there is an insert of more than 400 residues containing a PH domain, two SH2 domains, and one SH3 domain. The two conserved X and Y domains have been shown to be important for the catalytic activity. At the C-terminal of the Y-box, there is a C2 domain, possibly involved in Ca-dependent membrane attachment. PLCs show little similarity in the 300-residue N-terminal region preceding the X-domain.

1. Structural mapping of the catalytic mechanism for a mammalian phosphoinositide-specific phospholipase C. Biochemistry 36, 1704-18
2. A ternary metal binding site in the C2 domain of phosphoinositide-specific phospholipase C-delta1. Biochemistry 36, 2753-62
3. Regulation of inositol phospholipid-specific phospholipase C isozymes. J. Biol. Chem. 267, 12393-6
4. Regulation of phospholipase C by G proteins. Trends Biochem. Sci. 17, 502-6

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