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Title: 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, 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.

Authors:
 [1];  [2];  [3];  [4];  [4];  [1]
  1. Univ. of Connecticut, Storrs, CT (United States). Dept. of Physiology and Neurobiology
  2. Univ. of Connecticut Health Center, Farmington CT (United States). Pat and Jim Calhoun Center for Cardiology, Dept. of Cell Biology
  3. Oslo University Hospital and University of Oslo (Norway). Inst. for Experimental Medical Research
  4. Harvard Medical School, Boston, MA (United States). Dept. of Genetics; Harvard Univ., Boston, MA (United States). Wyss Inst. For Biologically Inspired Engineering
Publication Date:
Research Org.:
Harvard Univ., Cambridge, MA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Institutes of Health (NIH), National Institute Of Neurological Disorders and Stroke; University of Connecticut Research Foundation
OSTI Identifier:
1345186
Alternate Identifier(s):
OSTI ID: 1399283
Grant/Contract Number:
FG02-02ER63445
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
FEBS Letters
Additional Journal Information:
Journal Volume: 591; Journal Issue: 3; Related Information: Supplementary information files are available on the journal web site: http://onlinelibrary.wiley.com/doi/10.1002/1873-3468.12562/full in the Supporting Information section. They comprise three tables of proteomic and in vitro-derived data and an Appendix to the article.; Journal ID: ISSN 0014-5793
Publisher:
Federation of European Biochemical Societies
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cushing's syndrome; protein kinase A; substrate specificity; proteomic peptide library

Citation Formats

Lubner, Joshua M., Dodge-Kafka, Kimberly L., Carlson, Cathrine R., Church, George M., Chou, Michael F., and Schwartz, Daniel. Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity. United States: N. p., 2017. Web. doi:10.1002/1873-3468.12562.
Lubner, Joshua M., Dodge-Kafka, Kimberly L., Carlson, Cathrine R., Church, George M., Chou, Michael F., & Schwartz, Daniel. Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity. United States. doi:10.1002/1873-3468.12562.
Lubner, Joshua M., Dodge-Kafka, Kimberly L., Carlson, Cathrine R., Church, George M., Chou, Michael F., and Schwartz, Daniel. Wed . "Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity". United States. doi:10.1002/1873-3468.12562. https://www.osti.gov/servlets/purl/1345186.
@article{osti_1345186,
title = {Cushing's syndrome mutant PKAL205R exhibits altered substrate specificity},
author = {Lubner, Joshua M. and Dodge-Kafka, Kimberly L. and Carlson, Cathrine R. and Church, George M. and Chou, Michael F. and Schwartz, Daniel},
abstractNote = {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 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 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.},
doi = {10.1002/1873-3468.12562},
journal = {FEBS Letters},
number = 3,
volume = 591,
place = {United States},
year = {Wed Feb 01 00:00:00 EST 2017},
month = {Wed Feb 01 00:00:00 EST 2017}
}

Journal Article:
Free Publicly Available Full Text
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