The C2 domains of classical and novel PKCs as versatile decoders of membrane signals.
Corbalán-García S, Gómez-Fernández JC.
Biofactors. 2010 Jan-Feb;36(1):1-7. doi: 10.1002/biof.68. Review.

Abstract
The C2 domains of classical and novel protein kinases C play a very important role in decoding signals, which trigger the translocation of these enzymes to the plasma membrane and/or other membrane subcellular compartments. The C2 domain of classical PKCs has a long reputation as a paradigm of protein responding to intracytosolic Ca2+ elevations through a calcium-binding region, where this cation acts as a bridge with the phosphatidylserine located in the inner leaflet of the plasma membrane. However, more recently, it has been discovered that a second site on the C2 domain interacts specifically with the phosphoinositide, PtdIns(4,5)P(2). Furthermore, several in vivo studies have shown that both calcium and PtdIns(4,5)P(2)-interacting regions are essential for the translocation of classical PKCs to the membrane. Other molecules like arachidonic and retinoic acid have also been observed to bind to these domains, modulating the activity of classical PKCs. The C2 domains of novel PKCs, on the other hand, were supposed to play only a secondary role with respect to the C1 domain in the activation process of these enzymes. New insights reveal that these C2 domains may also receive regulatory inputs and play an important role in the localization and activation of these enzymes. In this way, the C2 domain of PKCepsilon has been observed to respond to phosphatidic acid and to act together with the C1 domain in the membrane anchorage and activation of the protein. These domains are also regulated by lipid-independent events like protein-protein interactions and phosphorylation. In this review we will focus in describing the recent findings on structural and functional properties of the C2 domains of PKCs, mainly as lipid-interacting modules able to integrate a wide variety of signals in the cell.

Signaling through C2 domains: more than one lipid target.
Corbalan-Garcia S, Gómez-Fernández JC.
Biochim Biophys Acta. 2014 Jun;1838(6):1536-47. doi: 10.1016/j.bbamem.2014.01.008. Epub 2014 Jan 16. Review.

Abstract
C2 domains are membrane-binding modules that share a common overall fold: a single compact Greek-key motif organized as an eight-stranded anti-parallel β-sandwich consisting of a pair of four-stranded β-sheets. A myriad of studies have demonstrated that in spite of sharing the common structural β-sandwich core, slight variations in the residues located in the interconnecting loops confer C2 domains with functional abilities to respond to different Ca(2+) concentrations and lipids, and to signal through protein-protein interactions as well. This review summarizes the main structural and functional findings on Ca(2+) and lipid interactions by C2 domains, including the discovery of the phosphoinositide-binding site located in the β3-β4 strands. The wide variety of functions, together with the different Ca(2+) and lipid affinities of these domains, converts this superfamily into a crucial player in many functions in the cell and more to be discovered. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.