Mycobacterium tuberculosis FasR senses long fatty acyl-CoA through a tunnel and a hydrophobic transmission spine

Julia Lara, Lautaro Diacovich, Felipe Trajtenberg, Nicole Larrieux, Emilio L. Malchiodi, Marisa M. Fernández, Gabriela Gago, Hugo Gramajo () and Alejandro Buschiazzo ()
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Julia Lara: Universidad Nacional de Rosario
Lautaro Diacovich: Universidad Nacional de Rosario
Felipe Trajtenberg: Institut Pasteur de Montevideo
Nicole Larrieux: Institut Pasteur de Montevideo
Emilio L. Malchiodi: Universidad de Buenos Aires
Marisa M. Fernández: Universidad de Buenos Aires
Gabriela Gago: Universidad Nacional de Rosario
Hugo Gramajo: Universidad Nacional de Rosario
Alejandro Buschiazzo: Institut Pasteur de Montevideo

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract Mycobacterium tuberculosis is a pathogen with a unique cell envelope including very long fatty acids, implicated in bacterial resistance and host immune modulation. FasR is a TetR-like transcriptional activator that plays a central role in sensing mycobacterial long-chain fatty acids and regulating lipid biosynthesis. Here we disclose crystal structures of M. tuberculosis FasR in complex with acyl effector ligands and with DNA, uncovering its molecular sensory and switching mechanisms. A long tunnel traverses the entire effector-binding domain, enabling long fatty acyl effectors to bind. Only when the tunnel is entirely occupied, the protein dimer adopts a rigid configuration with its DNA-binding domains in an open state, leading to DNA dissociation. The protein-folding hydrophobic core connects the two domains, and is completed into a continuous spine when the effector binds. Such a transmission spine is conserved in a large number of TetR-like regulators, offering insight into effector-triggered allosteric functional control.

Date: 2020
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DOI: 10.1038/s41467-020-17504-x

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