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bioRxiv · 10.1101/091231

Cushing’s Syndrome mutant PKAL205R exhibits altered substrate specificity

Lubner, J. M.·Dodge-Kafka, K. L.·Carlson, C. R.·Church, G. M.·Chou, M. F.·Schwartz, D.
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Abstract

The PKAL205R hotspot mutation has been implicated in Cushings Syndrome through hyperactive gain-of-function PKA signaling, however its influence on substrate specificity has not been investigated. Here, we employ the Proteomic Peptide Library (ProPeL) approach to create high-resolution models for PKAWT and PKAL205R substrate specificity. We reveal that the L205R mutation reduces canonical hydrophobic preference at the substrate P+1 position, and increases acidic preference in downstream positions. Using these models, we designed peptide substrates that exhibit altered selectivity for specific PKA variants, and demonstrate the feasibility of selective PKAL205R loss-of-function signaling. Through these results, we suggest that substrate rewiring may contribute to Cushings Syndrome disease etiology, and introduce a powerful new paradigm for investigating mutation-induced kinase substrate rewiring in human disease.

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Lubner, J. M., Dodge-Kafka, K. L., Carlson, C. R., Church, G. M., Chou, M. F., Schwartz, D.. 2016-12-05. Cushing’s Syndrome mutant PKAL205R exhibits altered substrate specificity. https://doi.org/10.1101/091231

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