Structure of the C2 domain from novel protein kinase Cε.: A membrane binding model for Ca 2+-independent C2 domains

Protein kinase C epsilon (PKC epsilon) is a member of the novel PKCs which are activated by acidic phospholipids, diacylglycerol and phorbol esters, but lack the calcium dependence of classical PKC isotypes. The crystal structures of the C2 domain of PKC epsilon, crystallized both in the absence and in the presence of the two acidic phospholipids, 1,2-dicaproyl-sn-phosphatidyl-L-serine (DCPS) and 1,2-dicaproyl-sn-phosphatidic acid (DCPA), have A resolution, respectively. The now been determined at 2.1, 1.7 and 2.8 Angstrom resolution, respectively. The central feature of the PKC epsilon -C2 domain structure is an eight-stranded, antiparallel, beta -sandwich with a type II topology similar to that of the C2 domains from phospholipase C and from novel PKC delta. Despite the similar, topology, important differences are found between the structures of C2 domains from PKCs delta and epsilon, suggesting they be considered as different PKC subclasses. Site-directed mutagenesis experiments and structural changes in the PKC epsilon -C2 domain from crystals with DCPS or DCPA indicate, though phospholipids were not visible in these structures, that loops joining strands beta1-beta2 and beta5-beta6 participate in the binding to anionic membranes. The different behavior in membrane-binding and activation between PKC epsilon and classical PKCs appears to originate in localized structural changes, which include a major reorganization of the region corresponding to the calcium binding pocket in classical PKCs. A mechanism is proposed for the interaction of the PKC epsilon -C2 domain with model membranes that retains basic features of the docking of C2 domains from classical, calcium-dependent, PKCs. (C) 2001 Academic Press.