Role of DAKAPs in Mitochondrial Function

点击翻译按钮获取中文摘要

Relatively little is known about second messenger signaling to mitochondria. In recent years though, a number of substrates have been identified in this organelle that are phosphorylated in a cAMP-dependent manner. These substrates have been identified in this organelle that are phosphorylated in a cAMP-dependent manner. These substrates including electron transport chain components and the proapoptotic protein, BAD, suggest a physiological role for cAMP-dependant protein kinase (PKA) in mitochondria. Experiments performed in the Taylor laboratory have identified two new AKAPs (D=AKAPs) are localized to the mitochondria. D-AKAP1 contains 30 amino acids at the NH2- terminus that are sufficient for targeting to the outer mitochondrial membrane, while preliminary studies suggest D-AKAP2 localizes to the matrix. Interestingly, D-AKAP2 also contains two putative PGS domains, sites capable of binding Galpha subunits and leading to speculation that D-AKAP2 may be a scaffolding protein capable of co- localizing multiple signaling molecules. We hypothesize that PKA's role in altering specific mitochondrial functions is mediated by its association with these novel anchoring proteins. To test this hypothesis, this research proposes to identify substrates phosphorylated by PKA as a consequence of this association with the AKAPs. Because of the biochemical differences between RI and RII isoforms, the relative effect of PKA on mitochondrial function may be a function of which isoform is bound to the anchoring protein. This research will thus seek to determine the relative significance of RI versus RII isoform anchoring in mitochondria. Finally, experiments will be performed to determine what proteins, in addition to PKA, are bound to D-AKAP2 in mitochondria.