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

• DOI: 10.1038/s41467-020-17504-x
• Publication Date: 2020-07-24T10:04:09Z
• Authors: Julia Lara; Lautaro Diacovich; Felipe Trajtenberg; Nicole Larrieux; Emilio L. Malchiodi; Marisa M. Fernández; Gabriela Gago; Hugo Gramajo; Alejandro Buschiazzo
• Keywords: Models, Molecular; TETR; TetR; MESH: Mycobacterium tuberculosis; Protein Conformation; FOS: Basic medicine; FOS: Health sciences; Crystallography, X-Ray; Ligands; Biochemistry; Gene; MESH: Protein Conformation; Cell Wall; https://purl.org/becyt/ford/1.6; MESH: Ligands; Pathology; TRANSCRIPTION FACTOR; MESH: Allosteric Site; MESH: Bacterial Proteins; 0303 health sciences; Q; Fatty Acids; Life Sciences; MESH: Transcription Factors; Allosteric regulation; MESH: Fatty Acids; 3. Good health; DNA-Binding Proteins; Chemistry; Infectious Diseases; Effector; Molecular Medicine; Medicine; MESH: Models, Molecular; Allosteric Site; Receptor; DNA, Bacterial; Cell biology; ACYL-COA; Science; TUBERCULOSIS; Article; Global Challenge of Antibiotic Resistance in Bacteria; 03 medical and health sciences; MESH: Cell Wall; Bacterial Proteins; MESH: Acyl Coenzyme A; Biochemistry, Genetics and Molecular Biology; Health Sciences; [CHIM.CRIS]Chemical Sciences/Cristallography; Genetics; Tuberculosis; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Protein folding; [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]; https://purl.org/becyt/ford/1; Biology; Bacterial Physiology and Genetics; Mycobacterium tuberculosis; MESH: Crystallography, X-Ray; MESH: DNA, Bacterial; [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology; FOS: Biological sciences; Repressor; Acyl Coenzyme A; Transcription factor; MESH: DNA-Binding Proteins; Transcription Factors

AbstractMycobacterium 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.