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Cushing’s Syndrome mutant PKAL205R exhibits altered substrate specificity

Joshua M. Lubner, Kimberly L. Dodge-Kafka, Cathrine R. Carlson, George M. Church, Michael F. Chou, Daniel Schwartz
doi: https://doi.org/10.1101/091231
Joshua M. Lubner
1Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA
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Kimberly L. Dodge-Kafka
2Pat and Jim Calhoun Center for Cardiology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030, USA
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Cathrine R. Carlson
3Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, 0407 Oslo, Norway
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George M. Church
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
5Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA
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Michael F. Chou
4Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
5Wyss Institute for Biologically Inspired Engineering, Boston, MA 02115, USA
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Daniel Schwartz
1Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269, USA
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Abstract

The PKAL205R hotspot mutation has been implicated in Cushing’s 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 Cushing’s Syndrome disease etiology, and introduce a powerful new paradigm for investigating mutation-induced kinase substrate rewiring in human disease.

Footnotes

  • Abbreviations: PKA, cAMP-dependent protein kinase A; ProPeL, Proteomic Peptide Library; P-site, phosphoacceptor-site; RIα, cAMP-dependent protein kinase type I-alpha regulatory subunit; PKI, cAMP-dependent protein kinase inhibitor alpha; CDK16, Cyclin-dependent kinase 16; ACN, acetonitrile; FA, formic acid

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted December 05, 2016.
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Cushing’s Syndrome mutant PKAL205R exhibits altered substrate specificity
Joshua M. Lubner, Kimberly L. Dodge-Kafka, Cathrine R. Carlson, George M. Church, Michael F. Chou, Daniel Schwartz
bioRxiv 091231; doi: https://doi.org/10.1101/091231
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Cushing’s Syndrome mutant PKAL205R exhibits altered substrate specificity
Joshua M. Lubner, Kimberly L. Dodge-Kafka, Cathrine R. Carlson, George M. Church, Michael F. Chou, Daniel Schwartz
bioRxiv 091231; doi: https://doi.org/10.1101/091231

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