Conformational switching on AKAP7 modulates the phosphorylation dynamics of anchored PKC

• DOI: 10.1096/fasebj.26.1_supplement.761.12
• Publication Date: 2021-06-21T15:41:44Z
• Authors: John M Redden; Eric Greenwald; Jeff Saucerman; Kimberly Dodge-Kafka
• Keywords: 0301 basic medicine; 03 medical and health sciences

The spatiotemporal fidelity of signal transduction is maintained in large part by scaffolding proteins. In particular, A‐Kinase Anchoring Proteins (AKAPs) accelerate and amplify the phosphorylation substrate proteins anchored kinases. However, mechanisms underlying these phenomena remain unclear. Our present study endeavors to clarify this mechanism utilizing a combination mathematical modeling, biochemistry, FRET microscopy. We propose model wherein enzymes on scaffold undergo “conformational switch” into an active intermediate. This predicts enzymatic reactions be accelerated, amplified, insulated from inhibition comparison those occuring solution. are exploring novel interaction between AKAP7α Protein Kinase C (PKC) as system validate predictions. preliminary data comparing responses genetically encoded PKC activity reporter (CKAR) AKAP7α‐CKAR fusion protein reveal that both speed strength CKAR enhanced when it tethered AKAP7α. Additionally, bound appears less susceptible several classes inhibitors, including ATP competitive inhibitor Gö6976 20–28. Collectively, our findings provide strong theoretical molecular evidence more narrowly defines anchoring hypothesis.