This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Carbon Catabolite Repression (CCR) is the global regulatory mechanism enabling bacteria to preferentially utilize the carbon source that is available in their environment. In E. coli and other enteric bacteria, CCR has been extensively studied since J. Monod first noted that E. coli prefer glucose as a carbon source. It was later shown that CCR in these bacteria is mediated through the DNA binding activator protein, cAMP receptor protein (CRP), which is induced to bind DNA in the presence of cAMP. It has more recently been demonstrated that Gram positive bacteria, which contain neither CRP nor cAMP, use an entirely different mechanism of CCR Specifically, in these bacteria, the master regulator of CCR is the transcription factor, the Carbon catabolite protein A (CcpA), a member of the LacI/GalR family. Underscoring its pleiotropic role, this protein regulates over 200 genes in Bacilli, accounting for over 8% of the entire Bacilli genome. In response to high levels of fructose 1,6-bisphosphate, HPr kinase phosphorylates the histidine-containing protein (HPr) at Serine 46. The Ser46 phosphorylated form of HPr binds CcpA and activates to bind its Cre DNA sites in the large CCR operon. Thus, phosphoSer46HPr functions as a corepressor for CcpA, providing the only example of a LacI/GalR member that is activated to bind DNA by binding another protein. To dissect the molecular mechanism whereby phosphoSer46Hpr can function as a corepressor and specifically interact with CcpA, we have obtained crystals of the ternary CcpA-phosphoSer46HPr-Cre site from B. megaterium. We have also grown crystals of CcpA in the absence of phosphoSer46Hpr or the Cre in order to obtain the non-activated as well as the activated conformational state of CcpA.

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Biotechnology Resource Grants (P41)
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