title: Genome-wide regulon and crystal structure of BlaI (Rv1846c) from Mycobacterium tuberculosis.
abstract: Comparative genomics with Staphylococcus aureus suggested the existence of a regulatory system governing beta-lactamase (BlaC) production in Mycobacterium tuberculosis. The crystal structure of Rv1846c, a winged helix regulator of previously unknown function, was solved thus revealing strong similarity to the BlaI and MecI repressors of S. aureus, which both respond to beta-lactam treatment. Using chromatin immunoprecipitation and hybridization to microarrays (ChIP-on-chip), the Rv1846c regulon was shown to comprise five separate genomic loci. Two of these mediate responses and resistance to beta-lactam antibiotics (rv1845c, rv1846c-rv1847; blaC-sigC); two encode membrane proteins of unknown function (rv1456c, rv3921c) while the last codes for ATP synthase (rv1303-atpBEFHAGDC-rv1312). The ChIP-on-chip findings were confirmed independently using electrophoretic mobility shift assays, DNAse footprinting and transcript analysis leading to Rv1846c being renamed BlaI. When cells were treated with beta-lactams, BlaI was released from its operator sites causing derepression of the regulon and upregulation of ATP synthase transcription. The existence of a potential regulatory loop between cell wall integrity and ATP production was previously unknown.
authors.affiliation: Global Health Institute, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sala
authors.forename: Ahmed
authors.initials: A
authors.lastname: Haouz
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Saul
authors.forename: Isabelle
authors.initials: I
authors.lastname: Miras
authors.forename: Ida
authors.initials: I
authors.lastname: Rosenkrands
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Alzari
authors.forename: Stewart T
authors.initials: ST
authors.lastname: Cole
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D018983:DNA Footprinting; D024202:Electrophoretic Mobility Shift Assay; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009169:Mycobacterium tuberculosis / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017433:Protein Structure, Secondary; D012329:RNA, Bacterial / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D018085:Regulon; D016415:Sequence Alignment; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism*; D047090:beta-Lactams / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D012329:RNA, Bacterial; D011994:Recombinant Proteins; D047090:beta-Lactams; D001618:beta-Lactamases