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Abstract
BackgroundPhosphatidylinositol 3-Kinases (PI3Ks) are a family of lipid kinases that phosphorylate the D3-hydroxyls of the inositol ring of phosphoinositides, and are responsible for coordinating a diverse range of cellular functions. A canonical pathway of activation of PI3Ks through the interaction of RA-domain with Ras proteins has been well established. In retinal photoreceptors, we have identified a non-canonical pathway of PI3Kγ activation through the interaction of its RA-domain with a putative Ras-like domain (RLD) in alpha subunit of cyclic nucleotide-gated channel (CNGA1) in retinal rod photoreceptors.ResultsThe interaction between PI3Kγ and CNGA1 does not appear to play a role in regulation of CNG channel activity, but PI3Kγ uses CNGA1 as an anchoring module to achieve close proximity to its substrate to generate D3-phosphoinositides.ConclusionsOur studies suggest a functional non-canonical PI3Kγ activation in retinal rod photoreceptor cells.
Highlights
Phosphatidylinositol 3-Kinases (PI3Ks) are a family of lipid kinases that catalyze the phosphorylation of D3hydroxyls in the inositol head group and generate several phosphorylated phosphoinositides [1]
PI3K interacts with CNGA1 We previously reported that the C-terminal region of CNGA1 displays 50-70% tertiary structural similarity towards Ras proteins [9]
Our studies suggest that growth factor receptor-bound protein 14 (Grb14), a Ras-associating (RA) domain-containing protein, binds to CNGA1 and modulates channel activity [10]
Summary
Phosphatidylinositol 3-Kinases (PI3Ks) are a family of lipid kinases that catalyze the phosphorylation of D3hydroxyls in the inositol head group and generate several phosphorylated phosphoinositides [1]. We found a non-canonical pathway of PI3Kγ activation through interaction of its RA-domain with a putative Ras-like domain (RLD) in the cyclic nucleotide-gated channel alpha subunit (CNGA1) in retinal rod photoreceptors. Photoreceptor cyclic nucleotide-gated (CNG) channels are critical elements in phototransduction and light adaptation [3,4]. Phosphatidylinositol 3-Kinases (PI3Ks) are a family of lipid kinases that phosphorylate the D3-hydroxyls of the inositol ring of phosphoinositides, and are responsible for coordinating a diverse range of cellular functions. We have identified a non-canonical pathway of PI3Kγ activation through the interaction of its RA-domain with a putative Ras-like domain (RLD) in alpha subunit of cyclic nucleotide-gated channel (CNGA1) in retinal rod photoreceptors
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