The C2 domains of classical and novel PKCs as versatile decoders of membrane signals

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.

Calpains and neuronal damage in the ischemic brain: The swiss knife in synaptic injury

“…The CBSW domain was formerly referred to as domain III or C2L domain because it is composed of eight anti-parallel β-strands that resemble the C2 domain found in other proteins, such as protein kinase C (PKC) and phospholipase C (PLC); however it was recently renamed CBSW because in its 3D structure this domain is not similar to the C2 domain. The CBSW domain is known to interact with Ca 2+ and phospholipids (Corbalan-Garcia and Gomez-Fernandez, 2010;Tompa et al, 2001;Vines, 2012).…”

Investigation of the Effect of Bilayer Composition on PKCα-C2 Domain Docking Using Molecular Dynamics Simulations

“…In full-length PKC α , the kinase domain is inhibited in solution by the C1 domains and it becomes active only through a multistep process of the C2 and C1 domains recognizing and binding to signaling lipids in the membrane. 5,17–24 …”

Cd2+as a Ca2+Surrogate in Protein–Membrane Interactions: Isostructural but Not Isofunctional

“…1–3 The changes in intracellular Ca 2+ levels are transduced to the membranes by two families of Ca 2+ effector proteins: annexins 4,5 and conserved homology-2 (C2) domains. 6–8 Both are peripheral membrane proteins that undergo membrane association in Ca 2+ -dependent manner, with specificity toward negatively charged phospholipids, such as phosphatidylserine (PtdSer). 9–11 …”