Allosteric coupling via distant disorder-to-order transitions.
Intrinsic disorder provides a means of maximizing allosteric coupling in proteins. However, the mechanisms by which the disorder functions in allostery remain to be elucidated. Small ligand, bio-5'-AMP, binding and dimerization of the Escherichia coli biotin repressor are allosterically coupled. Folding of a disordered loop in the allosteric effector binding site is required to realize the full coupling free energy of -4.0 ± 0.3 kcal/mol observed in the wild-type protein. Alanine substitution of a glycine residue on the dimerization surface that does not directly contribute to the dimerization interface completely abolishes this coupling. In this work, the structure of this variant, solved by X-ray crystallography, reveals a monomeric corepressor-bound protein. In the structure loops, neither of which contains the alanine substitution, on both the dimerization and effector binding surfaces that are folded in the corepressor-bound wild-type protein are disordered. The structural data combined with functional measurements indicate that allosteric coupling between ligand binding and dimerization in BirA (E. coli biotin repressor/biotin protein ligase) is achieved via reciprocal communication of disorder-to-order transitions on two distant functional surfaces.
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
Christopher
C
Eginton
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA.
William J
WJ
Cressman
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Sharrol
S
Bachas
Department of Biophysics and Biophysical Chemistry, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Herschel
H
Wade
Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, USA. Electronic address: dbeckett@umd.edu.
Dorothy
D
Beckett
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D000494:Allosteric Regulation; D000495:Allosteric Site; D001710:Biotin / Q000031:analogs & derivatives / Q000378:metabolism; D019731:Carbon-Nitrogen Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D017354:Point Mutation; D011485:Protein Binding; D011487:Protein Conformation; D060066:Protein Interaction Maps; D055503:Protein Multimerization; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
C082099:5'-AMP-biotin; D029968:Escherichia coli Proteins; D008024:Ligands; D012097:Repressor Proteins; D000249:Adenosine Monophosphate; D001710:Biotin; D019731:Carbon-Nitrogen Ligases; C058125:birA protein, E coli
allostery; coupled equilibria; disorder-to-order; protein:ligand interactions; protein:protein interactions