Cushing's syndrome mutant PKA<sup>L</sup><sup>205R</sup> exhibits altered substrate specificity.

TitleCushing's syndrome mutant PKAL205R exhibits altered substrate specificity.
Publication TypeJournal Article
Year of Publication2017
JournalFEBS letters
Volume591
Issue3
Pagination459-467
ISSN0014-5793
Abstract

The PKA 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 and PKA 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 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.

URLhttp://dx.doi.org/10.1002/1873-3468.12562
DOI10.1002/1873-3468.12562
Short TitleFEBS Lett
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