The Role of Post-Translational Modifications and Allostery in the Receptor Guanylyl Cyclases GC-A and GC-B

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The Role of Post-Translational Modifications and Allostery in the Receptor Guanylyl Cyclases GC-A and GC-B

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2018-12

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The receptor guanylyl cyclases (GC) GC-A and GC-B are complex transmembrane proteins with multiple functional domains and multiple post-translational modifications. GC-A and GC-B are activated by selective natriuretic peptide (NP) hormones binding to their glycosylated extracellular domains and primarily regulate the cardiovascular and skeletal systems, respectively. This binding signal then travels to a highly phosphorylated pseudokinase domain. The pseudokinase domain is phosphorylated prior to NP binding and must be phosphorylated for the binding signal to proceed further. Finally, the binding signal arrives at the guanylyl cyclase domain and simulates the production of cyclic guanosine monophosphate from guanosine triphosphate. Prior to my research there were many questions centered on the role of glycosylation in receptor maturation, the biological significance of phosphorylation and dephosphorylation, and the role of the pseudokinase domain and its potential interaction with ATP. We now know that dephosphorylation is a bona fide mechanism of regulation in vivo. Furthermore, ER-mediated glycosylation is required to generate a receptor that can be activated by NP and the only form of the enzyme correlated with GC activity is the most highly glycosylated form. Thus, mutations that inhibit full glycosylation of GC-B cause dwarfism. Finally, the pseudokinase domain functions as a conserved allosteric switch whose output is dependent on multiple input signals; NP binding, ATP binding, and phosphorylation. It accomplishes this integrative switch function through the dynamic assembly and disassembly of the regulatory spine and catalytic spine; hydrophobic core elements conserved in all kinases and pseudokinases. Together, my data substantially advances the field by providing a purpose to these post-translational modifications and a mechanistic function to the PKD.

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University of Minnesota Ph.D. dissertation. December 2018. Major: Biochemistry, Molecular Bio, and Biophysics. Advisors: Lincoln Potter, Timothy Griffin. 1 computer file (PDF); viii, 195 pages.

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Edmund, Aaron. (2018). The Role of Post-Translational Modifications and Allostery in the Receptor Guanylyl Cyclases GC-A and GC-B. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/209056.

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