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Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity.

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.

SUBMITTER: Lubner JM

PROVIDER: S-EPMC5321106 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity.

Lubner Joshua M JM Dodge-Kafka Kimberly L KL Carlson Cathrine R CR Church George M GM Chou Michael F MF Schwartz Daniel D

FEBS letters 20170203 3

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 posit ...[more]

PMID: 28100013

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