MALCHIODI Emilio Luis
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 MALCHIODI; MARISA FERNÁNDEZ; GABRIELA GAGO; HUGO GRAMAJO; ALEJANDRO BUSCHIAZZO
Springer Nature Editorial and Publishing
Lugar: Londres; Año: 2020
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 lipidbiosynthesis. We now 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. Structure-guided point-mutations further support this effector-dependent mechanism. 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 novel insight intoeffector-triggered allosteric functional control.