title: Structural basis for allosteric control of the transcription regulator CcpA by the phosphoprotein HPr-Ser46-P.
abstract: Carbon catabolite repression (CCR) is one of the most fundamental environmental-sensing mechanisms in bacteria and imparts competitive advantage by establishing priorities in carbon metabolism. In gram-positive bacteria, the master transcription regulator of CCR is CcpA. CcpA is a LacI-GalR family member that employs, as an allosteric corepressor, the phosphoprotein HPr-Ser46-P, which is formed in glucose-replete conditions. Here we report structures of the Bacillus megaterium apoCcpA and a CcpA-(HPr-Ser46-P)-DNA complex. These structures reveal that HPr-Ser46-P mediates a novel two-component allosteric DNA binding activation mechanism that involves both rotation of the CcpA subdomains and relocation of pivot-point residue Thr61, which leads to juxtaposition of the DNA binding regions permitting "hinge" helix formation in the presence of cognate DNA. The structure of the CcpA-(HPr-Ser46-P)-cre complex also reveals the elegant mechanism by which CcpA family-specific interactions with HPr-Ser46-P residues Ser46-P and His15 partition the high-energy CCR and low-energy PTS pathways, the latter requiring HPr-His15-P.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, Portland 97239, USA.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Schumacher
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Allen
authors.forename: Marco
authors.initials: M
authors.lastname: Diel
authors.forename: Gerald
authors.initials: G
authors.lastname: Seidel
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hillen
authors.forename: Richard G
authors.initials: RG
authors.lastname: Brennan
mesh_terms: D000494:Allosteric Regulation / Q000235:genetics; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence / Q000502:physiology; D001410:Bacillus megaterium / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006639:Histidine / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D010749:Phosphoprotein Phosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C069286:catabolite control proteins, bacteria; D013912:Threonine; D012694:Serine; D006639:Histidine; D004247:DNA; C110847:HPr kinase; D017346:Protein Serine-Threonine Kinases; D010749:Phosphoprotein Phosphatases