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Article

  • The EMBO Journal (2006) 25, 4074 - 4083
  • doi:10.1038/sj.emboj.7601284

Published online: 24 August 2006

Structural basis of lipid biosynthesis regulation in Gram-positive bacteria

Gustavo E Schujman1,2,a, Marcelo Guerin3,a, Alejandro Buschiazzo3, Francis Schaeffer3, Leticia I Llarrull1,4, Georgina Reh1,2, Alejandro J Vila1,4, Pedro M Alzari3 and Diego de Mendoza1,2

  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

Correspondence to:

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

aThese authors contributed equally to this work

Received 27 February 2006; Accepted 25 July 2006

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.

  • Keywords:

    • fatty acid synthesis,
    • Gram-positive bacteria,
    • lipid homeostasis,
    • malonyl-CoA,
    • X-ray crystallography