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Genome‐wide regulon and crystal structure of BlaI (Rv1846c) from Mycobacterium tuberculosis
Author(s) -
Sala Claudia,
Haouz Ahmed,
Saul Frederick A.,
Miras Isabelle,
Rosenkrands Ida,
Alzari Pedro M.,
Cole Stewart T.
Publication year - 2009
Publication title -
molecular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.857
H-Index - 247
eISSN - 1365-2958
pISSN - 0950-382X
DOI - 10.1111/j.1365-2958.2008.06583.x
Subject(s) - regulon , biology , repressor , chromatin immunoprecipitation , derepression , mycobacterium tuberculosis , genetics , gene , regulation of gene expression , microbiology and biotechnology , transcription factor , promoter , gene expression , tuberculosis , psychological repression , medicine , pathology
Summary 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.