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J. Biol. Chem., Vol. 281, Issue 10, 6793-6800, March 10, 2006
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1
From the
Department of Biochemistry & Molecular Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 and the
Lehrstuhl für Mikrobiologie, Institut für Mikrobiologie, Biochemie und Genetik der Friedrich-Alexander Universität Erlangen-Nürnberg, Staudstr. 5, 91058 Erlangen, Germany
In Gram-positive bacteria, the catabolite control protein A (CcpA) functions as the master transcriptional regulator of carbon catabolite repression/regulation (CCR). To effect CCR, CcpA binds a phosphoprotein, either HPr-Ser46-P or Crh-Ser46-P. Although Crh and histidine-containing protein (HPr) are structurally homologous, CcpA binds Crh-Ser46-P more weakly than HPr-Ser46-P. Moreover, Crh can form domain-swapped dimers, which have been hypothesized to be functionally relevant in CCR. To understand the molecular mechanism of Crh-Ser46-P regulation of CCR, we determined the structure of a CcpA-(Crh-Ser46-P)-DNA complex. The structure reveals that Crh-Ser46-P does not bind CcpA as a dimer but rather interacts with CcpA as a monomer in a manner similar to that of HPr-Ser46-P. The reduced affinity of Crh-Ser46-P for CcpA as compared with that of HPr-Ser46 P is explained by weaker Crh-Ser46-P interactions in its contact region I to CcpA, which causes this region to shift away from CcpA. Nonetheless, the interface between CcpA and helix
2 of the second contact region (contact region II) of Crh-Ser46-P is maintained. This latter finding demonstrates that this contact region is necessary and sufficient to throw the allosteric switch to activate cre binding by CcpA.
Received for publication, September 12, 2005 , and in revised form, November 18, 2005.
The atomic coordinates and structure factors (code 1ZVV for CcpA-(Crh-Ser46-P)-cre ternary complex) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).
* This work was supported in part by a Burroughs Wellcome Career Development Award 992863 (to M. A. S.) and the Deutsche Forschungsgemeinschaft through SFB 473 and the Fonds der Chemischen Industrie (to W. H.). The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, Materials Sciences Division, of the United States Department of Energy under contract DE-AC03-78SF00098 at the Lawrence Berkeley National Laboratory. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Robert A. Welch Distinguished University Chair in Chemistry. To whom correspondence should be addressed: Unit 1000, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-834-6390; Fax: 713-834-6397; E-mail: rgbrenna{at}mdanderson.org.
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