1. Mycobacterium tuberculosis FasR senses long fatty acyl-CoA through a tunnel, inducing DNA-dissociation via a transmission spine
- Author
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Marisa M. Fernández, Emilio L. Malchiodi, Felipe Trajtenberg, Gabriela Gago, Lautaro Diacovich, Nicole Larrieux, Alejandro Buschiazzo, Hugo Gramajo, and Julia Lara
- Subjects
0303 health sciences ,biology ,030306 microbiology ,Effector ,Allosteric regulation ,biology.organism_classification ,3. Good health ,Cell biology ,Mycobacterium tuberculosis ,03 medical and health sciences ,chemistry.chemical_compound ,Acyl-CoA ,chemistry ,Lipid biosynthesis ,TetR ,Transcription factor ,DNA ,030304 developmental biology - 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 two-domain transcriptional activator that belongs to the TetR family of regulators, and plays a central role in mycobacterial long-chain fatty acyl-CoA sensing and lipid biosynthesis regulation. We now disclose crystal structures of M. tuberculosis FasR in complex with acyl effector ligands and with DNA, uncovering its 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 that leads to DNA dissociation. Structure-guided point-mutations further support this effector-dependent mechanism. The protein-folding hydrophobic core, connecting the two domains, is completed by the effector ligand into a continuous spine, explaining the allosteric flexible-to-ordered transition. The transmission spine is conserved in all TetR-like transcription factors, offering new opportunities for anti-tuberculosis drug discovery.
- Published
- 2020
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