title: DevS oxy complex stability identifies this heme protein as a gas sensor in Mycobacterium tuberculosis dormancy.
abstract: DevS is one of the two sensing kinases responsible for DevR activation and the subsequent entry of Mycobacterium tuberculosis into dormancy. Full-length wild-type DevS forms a stable oxy-ferrous complex. The DevS autoxidation rates are extremely low (half-lives of >24 h) in the presence of cations such as K(+), Na(+), Mg(2+), and Ca(2+). At relatively high concentrations (100 mM), Cu(2+) accelerates autoxidation more than 1500-fold. Contrary to expectations, removal of the key hydrogen bond between the iron-coordinated oxygen and Tyr171 in the Y171F mutant provides a protein of comparable stability to autoxidation and similar oxygen dissociation rate. This correlates with our earlier finding that the Y171F mutant and wild-type kinase activities are similarly regulated by the binding of oxygen: namely, the ferrous five-coordinate complex is active, whereas the oxy-ferrous six-coordinate species is inactive. Our results indicate that DevS is a gas sensor in vivo rather than a redox sensor and that the stability of its ferrous-oxy complex is enhanced by interdomain interactions.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, 600 16th Street, San Francisco, California 94158-2517, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Ioanoviciu
authors.forename: Yergalem T
authors.initials: YT
authors.lastname: Meharenna
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Poulos
authors.forename: Paul R
authors.initials: PR
authors.lastname: Ortiz de Montellano
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites / Q000235:genetics; D005296:Ferrous Compounds / Q000737:chemistry / Q000378:metabolism; D006420:Hemeproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009169:Mycobacterium tuberculosis / Q000737:chemistry* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry / Q000378:metabolism*; D006656:Protamine Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D017434:Protein Structure, Tertiary / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D005296:Ferrous Compounds; D006420:Hemeproteins; D011994:Recombinant Proteins; C506260:DevS protein, Mycobacterium tuberculosis; D006656:Protamine Kinase; D010100:Oxygen