PT  - JOURNAL ARTICLE
AU  - Joshua M. Lubner
AU  - Kimberly L. Dodge-Kafka
AU  - Cathrine R. Carlson
AU  - George M. Church
AU  - Michael F. Chou
AU  - Daniel Schwartz
TI  - Cushing’s Syndrome mutant PKA<sup>L205R</sup> exhibits altered substrate specificity
AID  - 10.1101/091231
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 091231
4099  - http://biorxiv.org/content/early/2016/12/05/091231.short
4100  - http://biorxiv.org/content/early/2016/12/05/091231.full
AB  - 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.