In nature, microbes face a spectacular array of stimuli that challenge their survival. Collectively, these stimuli exert a strong selective pressure for th evolution of sophisticated, rapid-response mechanisms that can efficiently maintain homeostasis through the modulation of functions of diverse biomolecules. Not surprisingly, biologists are interested in understanding how these mechanisms work, how they are regulated, and how they are integrated into the cellular regulatory circuits. The PI's laboratory studies the control of protein function by chemical modifications, with an emphasis on reversible lysine acylation (RLA). Ten years ago, the PI's group reported the first evidence of RLA in prokaryotes, a discovery that elicited a great deal of interest. In a short period of time, RLA has emerged as a posttranslational modification that rivals phosphorylation in terms of its breadth and impact on the dynamics of the complex metabolic network of the cell. In recent years, the PI's group has reported the impact of RLA on central cellular processes such as cell motility, gene expression, carbon metabolism, energy and coenzyme A homeostasis. The PI's laboratory studies the control of protein function by RLA. The long-term goal of the work supported by grant R01-GM062203 is to understand the contributions of RLA to cell function. The PI's group will continue to apply comprehensive genetic, molecular biological, biochemical, structural, and system-wide approaches to answer fundamental questions regarding the mechanism of RLA function. Work proposed herein seeks to: i) learn the molecular details of how acetyltransferases recognize their protein substrates;ii) gain insights into the mechanism of acetyltransferase function;iii) gain a better understanding of how proteins evolve to escape RLA control;and iv) define the regulatory circuit that integrates RLA into the complex metabolic network of the cell.

Public Health Relevance

Reversible lysine acetylation (RLA) is a regulatory mechanism for the control of protein function that offers unique opportunities for improving human health and biotechnology. Our understanding of how RLA works, how it is regulated and integrated into the metabolic network, is very limited. The proposed work will fill gaps of basic knowledge about the system in these areas.

National Institute of Health (NIH)
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Prokaryotic Cell and Molecular Biology Study Section (PCMB)
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Gerratana, Barbara
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University of Georgia
Schools of Arts and Sciences
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Mitchell, Carter A; Tucker, Alex C; Escalante-Semerena, Jorge C et al. (2015) The structure of S. lividans acetoacetyl-CoA synthetase shows a novel interaction between the C-terminal extension and the N-terminal domain. Proteins 83:575-81
Crosby, Heidi A; Escalante-Semerena, Jorge C (2014) The acetylation motif in AMP-forming Acyl coenzyme A synthetases contains residues critical for acetylation and recognition by the protein acetyltransferase pat of Rhodopseudomonas palustris. J Bacteriol 196:1496-504
Tucker, Alex C; Escalante-Semerena, Jorge C (2014) Determinants within the C-terminal domain of Streptomyces lividans acetyl-CoA synthetase that block acetylation of its active site lysine in vitro by the protein acetyltransferase (Pat) enzyme. PLoS One 9:e99817
You, Di; Yao, Li-Li; Huang, Dan et al. (2014) Acetyl coenzyme A synthetase is acetylated on multiple lysine residues by a protein acetyltransferase with a single Gcn5-type N-acetyltransferase (GNAT) domain in Saccharopolyspora erythraea. J Bacteriol 196:3169-78
Tucker, Alex C; Escalante-Semerena, Jorge C (2013) Acetoacetyl-CoA synthetase activity is controlled by a protein acetyltransferase with unique domain organization in Streptomyces lividans. Mol Microbiol 87:152-67
Stuecker, Tara N; Hodge, Kelsey M; Escalante-Semerena, Jorge C (2012) The missing link in coenzyme A biosynthesis: PanM (formerly YhhK), a yeast GCN5 acetyltransferase homologue triggers aspartate decarboxylase (PanD) maturation in Salmonella enterica. Mol Microbiol 84:608-19
Crosby, Heidi A; Pelletier, Dale A; Hurst, Gregory B et al. (2012) System-wide studies of N-lysine acetylation in Rhodopseudomonas palustris reveal substrate specificity of protein acetyltransferases. J Biol Chem 287:15590-601
Chan, Chi Ho; Garrity, Jane; Crosby, Heidi A et al. (2011) In Salmonella enterica, the sirtuin-dependent protein acylation/deacylation system (SDPADS) maintains energy homeostasis during growth on low concentrations of acetate. Mol Microbiol 80:168-83
Thao, Sandy; Escalante-Semerena, Jorge C (2011) Biochemical and thermodynamic analyses of Salmonella enterica Pat, a multidomain, multimeric N(?)-lysine acetyltransferase involved in carbon and energy metabolism. MBio 2:
Thao, Sandy; Escalante-Semerena, Jorge C (2011) Control of protein function by reversible Nýý-lysine acetylation in bacteria. Curr Opin Microbiol 14:200-4

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