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

DOI: 10.1038/s41467-020-17504-x DOI Help

Authors: Julia Lara (Universidad Nacional de Rosario) , Lautaro Diacovich (Universidad Nacional de Rosario; Plataforma Argentina de Biología Estructural y Metabolómica (PLABEM)) , 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; Institut Pasteur, Paris)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: July 2020
Diamond Proposal Number(s): 19294

Open Access Open Access

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.

Journal Keywords: Bacterial physiology; Structural biology; Transcription

Diamond Keywords: Tuberculosis (TB); Bacteria

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I04-1-Macromolecular Crystallography (fixed wavelength)

Added On: 29/07/2020 14:02


Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Genetics Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)