Molecular evolution of a-kinase anchoring protein (AKAP)-7: implications in comparative PKA compartmentalization

BMC Evolutionary Biology

Robert S Danziger²  Graeme K Carnegie¹  Jessie Nicodemus-Johnson³  Keven R Johnson⁴ 

[1] Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA;Department of Cardiology, University of Illinois at Chicago, 840S. Wood Street, Chicago, IL 60612, USA;Department of Human Genetics, University of Chicago, Chicago, IL, USA;Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

关键词: AKAP15/18;    PKA compartmentalization;    PKA regulatory subunit;    Protein evolution;    A-Kinase anchoring protein;   

Others  :  1140773
DOI  :  10.1186/1471-2148-12-125

 received in 2011-12-30, accepted in 2012-07-10,  发布年份 2012

【 摘 要 】

Background

A-Kinase Anchoring Proteins (AKAPs) are molecular scaffolding proteins mediating the assembly of multi-protein complexes containing cAMP-dependent protein kinase A (PKA), directing the kinase in discrete subcellular locations. Splice variants from the AKAP7 gene (AKAP15/18) are vital components of neuronal and cardiac phosphatase complexes, ion channels, cardiac Ca²⁺ handling and renal water transport.

Results

Shown in evolutionary analyses, the formation of the AKAP7-RI/RII binding domain (required for AKAP/PKA-R interaction) corresponds to vertebrate-specific gene duplication events in the PKA-RI/RII subunits. Species analyses of AKAP7 splice variants shows the ancestral AKAP7 splice variant is AKAP7α, while the ancestral long form AKAP7 splice variant is AKAP7γ. Multi-species AKAP7 gene alignments, show the recent formation of AKAP7δ occurs with the loss of native AKAP7γ in rats and basal primates. AKAP7 gene alignments and two dimensional Western analyses indicate that AKAP7γ is produced from an internal translation-start site that is present in the AKAP7δ cDNA of mice and humans but absent in rats. Immunofluorescence analysis of AKAP7 protein localization in both rat and mouse heart suggests AKAP7γ replaces AKAP7δ at the cardiac sarcoplasmic reticulum in species other than rat. DNA sequencing identified Human AKAP7δ insertion-deletions (indels) that promote the production of AKAP7γ instead of AKAP7δ.

Conclusions

This AKAP7 molecular evolution study shows that these vital scaffolding proteins developed in ancestral vertebrates and that independent mutations in the AKAP7 genes of rodents and early primates has resulted in the recent formation of AKAP7δ, a splice variant of likely lesser importance in humans than currently described.

【 授权许可】

   
2012 Johnson et al.; licensee BioMed Central Ltd.

【 图 表 】

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