STRUCTURAL INSIGHTS INTO LIPID BIOSYNTHESIS REGULATION BY FAPR IN STAPHYLOCOCCUS AUREUS

ALBANESI, DANIELA; REH, GEORGINA; GUERIN, MARCELO E.; SCHAEFFER, FRANCIS; BUSCHIAZZO, ALEJANDRO; SCHUJMAN, GUSTAVO E.; ALZARI, PEDRO; DE MENDOZA, DIEGO

Santa Fe

Congreso; XLVIII Reunión Anual de la Asociación Argentina de Cristalografía; 2012

Asociación Argentina de Cristalografía

FapR is a transcription factor that negatively controls the expression of several genes of the fatty acid and phospholipid biosynthesis in Bacillus subtilis (the fap regulon). It is the first global regulator of lipid synthesis discovered in bacteria and is largely conserved in Gram positive organisms, including human pathogens as Bacillus anthracis, Listeria monocytogenes and Staphylococcus aureus[1]. FapR recognizes a consensus palindromic 17 bp sequence located in, or close to, the core promoter elements of all the transcriptional units that are members of the fap regulon and, upon binding, it protects approximately a 40 bp DNA region, which includes the 17 pb palindromic sequence. Malonyl-CoA acts as a negative effector of FapR promoting its release from DNA and the concomitant induction of the regulated promoters [1], [2]. Here we show that the function of FapR is conserved in S. aureus (SaFapR) and present the 3D structures of SaFapR in three relevant states of its regulation cycle: apo form, in complex with malonyl-CoA and in complex with DNA. The structural analysis shed light into the molecular mechanisms by which malonyl-CoA modulates the DNA-binding activity of the repressor. Notably, disruption of the ability of SaFapR to monitor malonyl-CoA compromises cell growth, revealing the essentiality of membrane lipid homeostasis for S. aureus survival. The detailed understanding of this modulation mechanism not only provides unique opportunities to learn how Gram-positive bacteria monitor the status of fatty acid biosynthesis and adjust the lipid synthesis accordingly, but also constitutes the basis for the development of novel antibacterial compounds with potential therapeutic applications.   [1] Schujman GE, Paoletti L, Grossman AD, de Mendoza D. (2003). FapR, a bacterial transcription factor involved in global regulation of membrane lipid biosynthesis. Dev. Cell. 4: 663-672. [2] Schujman GE, Guerin M, Buschiazzo A, Schaeffer F, Llarrull LI, Reh G, Vila AJ, Alzari PM, de Mendoza D. (2006). Structural basis of lipid biosynthesis regulation in Grampositive bacteria. EMBO J 25: 4074-4083.