Cushing's syndrome mutant PKA^L205R exhibits altered substrate specificity.

ABSTRACT: The PKA^L205R 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 PKA^WT and PKA^L205R 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 PKA^L205R loss-of-function signaling. Through these results,

SUBMITTER: Lubner JM 

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

REPOSITORIES: biostudies-literature