Fig. 5
The proposed mechanism of iPLA2β regulation and macromolecular interactions. a Schematic representation of the iPLA2β dimer in a hypothetical inhibited state bound to CaM. CAT domains are shown in blue and yellow, ANK domains in navy and orange, and a single CaM molecule is represented by two connected circles in pink. Active site cavities are represented by narrow channels (gray lines) leading from the solvent-exposed surface to the Ser/Asp catalytic dyad depicted by magenta. b An active conformation of the dimer. CaM dissociation leads to the opening of the active sites. ANK domains are available for interactions with protein partners as illustrated for CAMKIIβ (light cyan transparent sphere), known to interact with ANK domain, and with transmembrane Cnx (shown as transmembrane helix with the C-terminal cytosolic peptide in pale yellow), which could recruit iPLA2β to the membrane. The Cnx-binding site of iPLA2β is not known and the hypothetical interaction with ANK domain is based on similar interaction of AnkB and sodium channel peptide. ATP binding (red) in the middle of the ANK domain could trigger additional conformational changes of the AR. Acylation of C651 by oleoyl-coA (green) can facilitate interaction with the membrane and/or opening of active site channels. Other conformational states are feasible as well, such as CaM-bound inhibited protein at the membrane or an open conformation of active sites in CaM-free form in cytosol, corresponding to the crystallized form
