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Proc Natl Acad Sci U S A. 2014 Mar 4;111(9):3442-7. doi: 10.1073/pnas.1315281111. Epub 2014 Feb 18.

Gene regulation by substoichiometric heterocomplex formation of undecameric TRAP and trimeric anti-TRAP.

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Department of Chemistry and Biochemistry, Biophysics Graduate Program, and Center for RNA Biology, College of Pharmacy, The Ohio State University, Columbus, OH 43210.


The control of tryptophan production in Bacillus is a paradigmatic example of gene regulation involving the interplay of multiple protein and nucleic acid components. Central to this combinatorial mechanism are the homo-oligomeric proteins TRAP (trp RNA-binding attenuation protein) and anti-TRAP (AT). TRAP forms undecameric rings, and AT assembles into triskelion-shaped trimers. Upon activation by tryptophan, the outer circumference of the TRAP ring binds specifically to a series of tandem sequences present in the 5' UTR of RNA transcripts encoding several tryptophan metabolism genes, leading to their silencing. AT, whose expression is up-regulated upon tryptophan depletion to concentrations not exceeding a ratio of one AT trimer per TRAP 11-mer, restores tryptophan production by binding activated TRAP and preventing RNA binding. How the smaller AT inhibitor prevents RNA binding at such low stoichiometries has remained a puzzle, in part because of the large RNA-binding surface on the tryptophan-activated TRAP ring and its high affinity for RNA. Using X-ray scattering, hydrodynamic, and mass spectrometric data, we show that the polydentate action of AT trimers can condense multiple intact TRAP rings into large heterocomplexes, effectively reducing the available contiguous RNA-binding surfaces. This finding reveals an unprecedented mechanism for substoichiometric inhibition of a gene-regulatory protein, which may be a widespread but underappreciated regulatory mechanism in pathways that involve homo-oligomeric or polyvalent components.


NMR; minimal ensembles; native mass spectrometry; reversible oligomerization; small-angle X-ray scattering

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