TY - JOUR
T1 - Structural basis for cAMP-mediated allosteric control of the catabolite activator protein
AU - Popovych, Nataliya
AU - Tzeng, Shiou Ru
AU - Tonelli, Marco
AU - Ebright, Richard H.
AU - Kalodimos, Charalampos G.
PY - 2009/4/28
Y1 - 2009/4/28
N2 - The cAMP-mediated allosteric transition in the catabolite activator protein (CAP; also known as the cAMP receptor protein, CRP) is a textbook example of modulation of DNA-binding activity by small-molecule binding. Here we report the structure of CAP in the absence of cAMP, which, together with structures of CAP in the presence of cAMP, defines atomic details of the cAMP-mediated allosteric transition. The structural changes, and their relationship to cAMP binding and DNA binding, are remarkably clear and simple. Binding of cAMP results in a coil-to-helix transition that extends the coiled-coil dimer-ization interface of CAP by 3 turns of helix and concomitantly causes rotation, by ≈ 60°, and translation, by 7 Å, of the DNA-binding domains (DBDs) of CAP, positioning the recognition helices in the DBDs in the correct orientation to interact with DNA. The allosteric transition is stabilized further by expulsion of an aromatic residue from the cAMP-binding pocket upon cAMP binding. The results define the structural mechanisms that underlie allosteric control of this prototypic transcriptional regulatory factor and provide an illustrative example of how effector-mediated structural changes can control the activity of regulatory proteins.
AB - The cAMP-mediated allosteric transition in the catabolite activator protein (CAP; also known as the cAMP receptor protein, CRP) is a textbook example of modulation of DNA-binding activity by small-molecule binding. Here we report the structure of CAP in the absence of cAMP, which, together with structures of CAP in the presence of cAMP, defines atomic details of the cAMP-mediated allosteric transition. The structural changes, and their relationship to cAMP binding and DNA binding, are remarkably clear and simple. Binding of cAMP results in a coil-to-helix transition that extends the coiled-coil dimer-ization interface of CAP by 3 turns of helix and concomitantly causes rotation, by ≈ 60°, and translation, by 7 Å, of the DNA-binding domains (DBDs) of CAP, positioning the recognition helices in the DBDs in the correct orientation to interact with DNA. The allosteric transition is stabilized further by expulsion of an aromatic residue from the cAMP-binding pocket upon cAMP binding. The results define the structural mechanisms that underlie allosteric control of this prototypic transcriptional regulatory factor and provide an illustrative example of how effector-mediated structural changes can control the activity of regulatory proteins.
KW - Allosteric regulation
KW - Gene regulation
KW - NMR structure
KW - Protein NMR
KW - cAMP binding
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U2 - 10.1073/pnas.0900595106
DO - 10.1073/pnas.0900595106
M3 - Article
C2 - 19359484
AN - SCOPUS:66349083528
SN - 0027-8424
VL - 106
SP - 6927
EP - 6932
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 17
ER -