Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity. Issue 3 (3rd February 2017)

• Record Type: Journal Article
• Authors: Lubner, Joshua M.; Dodge‐Kafka, Kimberly L.; Carlson, Cathrine R.; Church, George M.; Chou, Michael F.; Schwartz, Daniel
• Is Part Of: FEBS letters. Volume 591:Issue 3(2017)
• Page Start: 459
• Page End: 467
• Publication Date: 2017-02-03
• Subjects: Cushing's syndrome -- protein kinase A -- substrate specificity; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1002/1873-3468.12562
• Languages: English
• ISSNs: 0014-5793

Abstract

Abstract : The PKA L 205R 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 L 205R 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 L 205R 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. Abstract :