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| Subject Categories: Cellular Metabolism | Structural Biology |
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| The EMBO Journal
(2006) 25, 4074–4083, doi:10.1038/sj.emboj.7601284 Published online 24 August 2006 |
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| Structural basis of lipid biosynthesis regulation in Gram-positive bacteria |
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| Gustavo E Schujman1, 2, 5, Marcelo Guerin3, 5, Alejandro Buschiazzo3, Francis Schaeffer3, Leticia I Llarrull1, 4, Georgina Reh1, 2, Alejandro J Vila1, 4, Pedro M Alzari3 and Diego de Mendoza1, 2 |
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1 Instituto de Biología Molecular y Celular de Rosario (IBR), Universidad Nacional de Rosario, Rosario, Argentina 2 Departamento de Microbiología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, Rosario, Argentina 3 Unité de Biochimie Structurale & URA 2185 CNRS, Institut Pasteur, Paris, France 4 Departamento de Química Biológica, Área Biofísica, Universidad Nacional de Rosario, Rosario, Argentina To whom correspondence should be addressed Pedro M Alzari, Unité de Biochimie Structurale, Institut Pasteur, URA 2185 CNRS, 25 rue du Docteur Roux, Paris 75724, France. Tel.: +33 1 4568 8607; Fax: +33 1 4568 8604; E-mail: alzari@pasteur.fr Diego de Mendoza, IBR-CONICET, Suipacha 531, Rosario 2000, Argentina. Tel.: +54 341 435 1235 ext 111; Fax: +54 341 439-0465; E-mail: demendoza@ibr.gov.ar 5 These authors contributed equally to this work Received 27 February 2006; Accepted 25 July 2006; Published online 24 August 2006. |
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| Abstract |
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| Malonyl-CoA is an essential intermediate in fatty acid synthesis in all living cells. Here we demonstrate a new role for this molecule as a global regulator of lipid homeostasis in Gram-positive bacteria. Using in vitro transcription and binding studies, we demonstrate that malonyl-CoA is a direct and specific inducer of Bacillus subtilis FapR, a conserved transcriptional repressor that regulates the expression of several genes involved in bacterial fatty acid and phospholipid synthesis. The crystal structure of the effector-binding domain of FapR reveals a homodimeric protein with a thioesterase-like 'hot-dog' fold. Binding of malonyl-CoA promotes a disorder-to-order transition, which transforms an open ligand-binding groove into a long tunnel occupied by the effector molecule in the complex. This ligand-induced modification propagates to the helix-turn-helix motifs, impairing their productive association for DNA binding. Structure-based mutations that disrupt the FapR–malonyl-CoA interaction prevent DNA-binding regulation and result in a lethal phenotype in B. subtilis, suggesting this homeostatic signaling pathway as a promising target for novel chemotherapeutic agents against Gram-positive pathogens. |
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| Keywords: fatty acid synthesis, Gram-positive bacteria, lipid homeostasis, malonyl-CoA, X-ray crystallography |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSSolving an old puzzle in phospholipid biosynthesis Nature Chemical Biology News and Views (01 Nov 2006) The Lego-ization of polyketide biosynthesis Nature Biotechnology News and Views (01 Sep 2005) RESEARCHStructural basis of lipid biosynthesis regulation in Gram-positive bacteria The EMBO Journal Article Nature Biotechnology Research (01 Sep 2007) |
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