Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 40, Pages 27480-27486Publisher
ELSEVIER
DOI: 10.1074/jbc.M109.011312
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Funding
- National Institutes of Health [R01 CA071649, DK063069, AI076961, AI081982, AI2008031, AI072106, AI068730, GM037684, GM020501, GM066170]
- Innovative Technologies for the Molecular Analysis of Cancer (IMAT) Program [CA099835, CA118595]
- University of California IUCRP Program
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Rap1b has been implicated in the transduction of the cAMP mitogenic response. Agonists that increase intracellular cAMP rapidly activate (i.e. GTP binding) and phosphorylate Rap1b on Ser(179) at its C terminus. cAMP-dependent protein kinase (PKA)-mediated phosphorylation of Rap1b is required for cAMP-dependent mitogenesis, tumorigenesis, and inhibition of AKT activity. However, the role of phosphorylation still remains unknown. In this study, we utilized amide hydrogen/deuterium exchange mass spectroscopy (DXMS) to assess potential conformational changes and/or mobility induced by phosphorylation. We report here DXMS data comparing exchange rates for PKA phosphorylated (Rap1-P) and S179D phosphomimetic (Rap1-D) Rap1b proteins. Rap1-P and Rap1-D behaved exactly the same, revealing an increased exchange rate in discrete regions along the protein; these regions include a domain around the phosphorylation site and unexpectedly the two switch loops. Thus, local effects induced by Ser(179) phosphorylation communicate allosterically with distal domains involved in effector interaction. These results provide a mechanistic explanation for the differential effects of Rap1 phosphorylation by PKA on effector protein interaction.
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