Figure 1.

Primary structure of protein kinase C (PKC) family members. All PKC isoforms contain an autoinhibitory pseudosubstrate peptide (green) and a carboxy-terminal kinase core (blue). The kinase core contains three phosphorylation/autophosphorylation sites (pink) critical for maturation: the activation loop, turn motif, and hydrophobic motif (numbering shown for cPKCβ, nPKCδ, and aPKCζ; note that the hydrophobic motif site is a Glu in aPKC isoforms). PKC isoforms are grouped according to their regulatory domains: cPKC isoforms contain two tandem DAG-sensitive C1 domains (orange) and a Ca²⁺-sensitive C2 domain (yellow); nPKC isoforms contain two tandem DAG-sensitive C1 domains and a novel, Ca²⁺-insensitive C2 domain; and aPKC isoforms contain a PB-1 (phox and bem-1) protein-protein interaction module (red) and an atypical, DAG-insensitive C1 domain. The C1 domains of all PKC isoforms interact with PS, and the C2 domains of cPKC isoforms interact non-specifically with anionic phospholipids, including PS. Critical features underlying responsiveness to second messengers are highlighted: Tyr (Y) at position 22 in the C1b domain of cPKC isoforms confers weak DAG responsiveness; Trp (W) at position 22 in the C1b domain of nPKC isoforms confers strong DAG responsiveness; and a basic patch (++) in the C2 domain of cPKC isoforms (located distal to the Ca²⁺-dependent lipid binding site) specifically recognizes PIP₂.