6d2s
Mycobacterium tuberculosis transcriptional regulator
Structural highlights
FunctionPRPR_MYCTU Plays a key role in regulating expression of enzymes involved in the catabolism of short chain fatty acids (SCFA) via both the glyoxylate (acetyl degradation route) and the methylcitrate cycle (propionate degradation route) (PubMed:22916289, PubMed:24705740). Required for intracellular growth in macrophages and for the assimilation of cholesterol-derived propionate (PubMed:22365605). PrpR acts as a transcriptional activator of prpDC and icl genes when propionate is the main carbon source, and as a ramB repressor (PubMed:22916289). During growth on propionate, PrpR also acts as a transcriptional repressor of dnaA, which encodes the DnaA initiator protein responsible for initiating chromosomal replication (PubMed:24705740). It is possibly involved in the regulation of genes responsible for controlling cholesterol utilization (PubMed:22365605).[1] [2] [3] Publication Abstract from PubMedThe pathogenicity of Mycobacterium tuberculosis depends upon its ability to catabolize host cholesterol. Upregulation of the methylcitrate cycle (MCC) is required to assimilate and detoxify propionyl-CoA, a cholesterol degradation product. The transcription of key genes prpC and prpD in MCC is activated by MtPrpR, a member of a family of prokaryotic transcription factors whose structures and modes of action have not been clearly defined. We show that MtPrpR has a novel overall structure and directly binds to CoA or short-chain acyl-CoA derivatives to form a homotetramer that covers the binding cavity and locks CoA tightly inside the protein. The regulation of this process involves a [4Fe4S] cluster located close to the CoA-binding cavity on a neighboring chain. Mutations in the [4Fe4S] cluster binding residues rendered MtPrpR incapable of regulating MCC gene transcription. The structure of MtPrpR without the [4Fe4S] cluster-binding region shows a conformational change that prohibits CoA binding. The stability of this cluster means it is unlikely a redox sensor but may function by sensing ambient iron levels. These results provide mechanistic insights into this family of critical transcription factors who share similar structures and regulate gene transcription using a combination of acyl-CoAs and [4Fe4S] cluster. Structural and functional insight into the Mycobacterium tuberculosis protein PrpR reveals a novel type of transcription factor.,Tang S, Hicks ND, Cheng YS, Silva A, Fortune SM, Sacchettini JC Nucleic Acids Res. 2019 Oct 10;47(18):9934-9949. doi: 10.1093/nar/gkz724. PMID:31504787[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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