Activation and Inhibition Mechanisms of Membrane Guanylyl Cyclases

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Activation and Inhibition Mechanisms of Membrane Guanylyl Cyclases

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2013-04

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Guanylyl cyclase (GC)-A and GC-B are homologous enzymes that catalyze the formation of cyclic guanosine monophosphate and pyrophosphate from GTP. GC-A is activated by atrial natriuretic peptide and B-type natriuretic peptide and regulates the cardiovascular system. GC-B is activated by C-type natriuretic peptide and regulates the skeletal and female reproductive systems. Activation of GC-A and GC-B was hypothesized to occur through two steps, binding of natriuretic peptide and subsequent binding of ATP to the kinase homology domain. However, our group reported that ATP binding does not increase maximal velocity but reduces the Michaelis constant. My work revealed an allosteric ATP binding site in the catalytic domain. Mutation and structure/function studies indicated that the allosteric and catalytic sites are different and that GC-A and GC-B are asymmetric homodimers, not symmetric homodimers as had been previously suggested. Interestingly, a constitutively active mutant of GC-B mimicked an ATP bound state. ATP inhibits soluble guanylyl cyclases (sGC), and I demonstrated that physiological concentrations of ATP inhibit GC-A and GC-B. I went on to determine that the mechanism of inhibition was through binding the pyrophosphate-product site. Together, these data revealed how low and high concentrations of ATP activate and inhibit GC-A and GC-B, respectively.

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University of Minnesota Ph.D. dissertation. April 2013. Major: Pharmacology. Advisor: Lincoln Potter. 1 computer file (PDF); vi, 232 pages.

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Robinson, Jerid. (2013). Activation and Inhibition Mechanisms of Membrane Guanylyl Cyclases. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/173946.

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