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Grayce B. Kerr Centennial Chair, Chemistry and Biochemistry Office: Stephenson Life Sciences Research Center 2590 Lab: Stephenson Life Sciences Research Center 2600 Office phone: 405-325-1529 awest at ou dot edu https://www.ou.edu/content/cas/chemistry/directory/faculty/ann-west.html
Ph.D., Genetics - Yale University, 1991
In prokaryotic organisms, adaptive responses to environmental changes such as nutrient limitation, oxygen deprivation, and osmotic shock are regulated by so-called two-component signal transduction pathways. These systems have in common a biochemical strategy involving phosphoryl transfer between two protein components: a histidine protein kinase and a response regulator protein. The histidine kinase is typically a transmembrane receptor that upon ligand stimulation undergoes autophosphorylation of a specific histidine residue within the cytoplasmic signaling domain. The phosphoryl group is then transferred to a specific aspartic acid residue on the response regulator protein. Phosphorylation of the response regulator results in the activation of either an associated or downstream effector function. For several decades, two-component signal transduction pathways were thought to be restricted to the bacterial kingdom. However, it is now recognized that eukaryotic organisms, such as plants and fungi, have proteins that are homologous to the bacterial histidine kinases and response regulators. With higher complexity than typical two-component signaling pathways, osmoregulation in the yeast, Saccharomyces cerevisiae, is mediated by a multi-step phosphorelay mechanism involving three proteins, the SLN1 sensor histidine kinase, the phosphorelay protein YPD1, and the response regulator SSK1. SSK1 serves to activate a downstream mitogen-activated protein (MAP) kinase cascade. The West Group is interested in elucidating the role of phosphorylation and dephosphorylation in regulating protein function within the yeast phosphorelay signaling pathway. Experiments are directed at biochemical characterization of the phosphoryl transfer reactions mediated by SLN1, YPD1, and SSK1, and elucidation of protein structures by X-ray crystallography. Since these pathway components are not found in humans, they represent novel targets for potential antifungal drug development.
Kennedy, E.N., Hebdon, S.D., Menon, S.K., Foster, C.A., Copeland, D.M., Xu, Q., Janiak-Spens, F. and West, A.H. (2019) Role of the highly conserved G68 residue in the yeast phosphorelay protein Ypd1: implications for interactions between histidine phosphotransfer (HPt) and response regulator proteins. BMC Biochemistry 20: 1.
Hebdon, S. D., Menon, S. K., Richter-Addo, G. B., Karr, E. A. and West, A. H. (2018) Regulatory targets of the response regulator CDR20291_1586 from Clostridioides difficile identified using a bacterial one-hybrid screen. J. Bacteriol. 200(23): e00351-18.
Foster, C. A. and West, A. H. (2017) Use of restrained molecular dynamics to predict the conformations of phosphorylated receiver domains in two-component signaling systems. Proteins: Struct., Funct., and Bioinf. 85: 155-176.
Kennedy, E., Menon, S. and West, A. H. (2016) Extended N-terminal region of the essential phosphorelay signaling protein Ypd1 from Cryptococcus neoformans contributes to structural stability, phospho-stability and binding of calcium ions. FEMS Yeast Research 16: doi: 10.1093/femsyr/fow068.
Wang, B., Powell, S. M., Hessami, N., Najar, F. Z., Thomas, L. M., Karr, E. A., West, A. H. and Richter-Addo, G. B. (2016) Crystal structures of two nitroreductases from hypervirulent Clostridium difficile and functionally related interactions with the antibiotic metronidazole. Nitric Oxide: Biol. Chem. 60: 32-39.
Isom, C. E., Menon, S. K., Thomas, L. M., West, A. H., Richter-Addo, G. B. and Karr, E. A. (2016) Crystal structure and DNA binding behavior of a PadR family transcription regulator from hypervirulent Clostridium difficile R20291. BMC Microbiol. 16: 231.
Fassler, J. S. and West, A. H. (2013) Histidine phosphotransfer proteins in fungal two-component signal transduction pathways. Euk. Cell 12(8): 1052-1060.
Fassler, J. S. and West, A. H. (2011) Fungal Skn7 stress responses and the relationship to virulence. Euk. Cell 10: 156-167.
Kaserer, A. O, Andi, B., Cook, P. F., and West, A. H. (2010) Kinetic studies of the yeast His-Asp phosphorelay signaling pathway. Meth. Enzymol. 471: 59-75.
Fassler, J. S. and West, A. H. (2010) Genetic and biochemical analysis of the SLN1 pathway in Saccharomyces cerevisiae. Meth. Enzymol. 471: 291-317.