Structural Insights into Phospholipase C-βFunction

Abstract

Phospholipase C (PLC) enzymes convert phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol-1,4,5-triphosphate. The production of these molecules promotes the release of intracellular calcium and activation of protein kinase C, which results in profound cellular changes. The PLCb subfamily is of particular interest given its prominent role in cardiovascular and neuronal signaling and its regulation by G protein-coupled receptors, as PLCb is the canonical downstream target of the heterotrimeric G protein Ga q . However, this is not the only mechanism regulating PLCb activity. Extensive structural and biochemical evidence has revealed regulatory roles for autoinhibitory elements within PLCb, Gbg, small molecular weight G proteins, and the lipid membrane itself. Such complex regulation highlights the central role that this enzyme plays in cell signaling. A better understanding of the molecular mechanisms underlying the control of its activity will greatly facilitate the search for selective small molecule modulators of PLCb.

M3 Muscarinic Receptor Interaction with Phospholipase C β3 Determines Its Signaling Efficiency

“…Previous studies of PLC␤ plasma membrane binding suggest that the C-terminal domain of PLC␤ isoforms may participate in an ionic interaction with the negatively charged inner surface of the PM to drive partial membrane association (35,(43)(44)(45)(46). The data here, in combination with others, show that PLC␤3 does not associate with the plasma membrane unless M3R is coexpressed (Fig.…”

“…The distal C-terminal domain of PLC␤3 has been suggested to coordinate interactions with the membrane and the N terminus of G␣ q so that optimum PLC␤3 activation could be attained (45,46). An intact PLC␤3 C-terminal domain is coincidentally required for PLC␤3 binding to M3R (Figs.…”

Membrane-induced Allosteric Control of Phospholipase C-β Isozymes

“…This difference in rate enhancements reflects the preferential capacity of the XY-linker to mediate autoinhibition that is dependent on the vesicle surface, probably through a combination of electrostatic repulsion created by the cap and steric occlusion formed by the plug of the XY-linker. Recent structural and biochemical work suggests that this model is overly simple (39). Structures of two cephalopod PLC-␤ isozymes highlighted a short extension of the C2 domain that interacts with the catalytic TIM barrel but not within the lipase active site (35).…”

Phospholipase Cβ1 induces membrane tubulation and is involved in caveolae formation

“…Liposomes. Similar to other PLCs, PLCβ contains a catalytic core composed of an N-terminal PH domain, EF-hand motif, and the active sites X and Y, followed by a C2 domain (27). In addition to the catalytic X and Y domains, PLCβ is characterized by the presence of an extended C terminus of ∼400 amino acids (Fig.…”

“…3A). This C-terminal extension contains a highly conserved Gα q binding site (28) and an elongated ∼300-amino acid coiled-coil domain (27). Whereas the PLCδ PH domain binds PIP 2 with high specificity and affinity, the binding of the PLCβ PH domain to the lipid is weak (29,30).…”