Direct observation of the dynamic process underlying allosteric signal transmission.
Allosteric regulation is an effective mechanism of control in biological processes. In allosteric proteins a signal originating at one site in the molecule is communicated through the protein structure to trigger a specific response at a remote site. Using NMR relaxation dispersion techniques we directly observe the dynamic process through which the KIX domain of CREB binding protein communicates allosteric information between binding sites. KIX mediates cooperativity between pairs of transcription factors through binding to two distinct interaction surfaces in an allosteric manner. We show that binding the activation domain of the mixed lineage leukemia (MLL) transcription factor to KIX induces a redistribution of the relative populations of KIX conformations toward a high-energy state in which the allosterically activated second binding site is already preformed, consistent with the Monod-Wyman-Changeux (WMC) model of allostery. The structural rearrangement process that links the two conformers and by which allosteric information is communicated occurs with a time constant of 3 ms at 27 degrees C. Our dynamic NMR data reveal that an evolutionarily conserved network of hydrophobic amino acids constitutes the pathway through which information is transmitted.
Brüschweiler
Sven
S
Department of Computational & Structural Biology, Max F. Perutz Laboratories, Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
Schanda
Paul
P
Kloiber
Karin
K
Brutscher
Bernhard
B
Kontaxis
Georg
G
Konrat
Robert
R
Tollinger
Martin
M
D001665:Binding Sites; D050882:CREB-Binding Protein / Q000737:chemistry* / Q000378:metabolism; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry* / Q000378:metabolism; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D020598:Proto-Oncogene Proteins c-myb / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
D020598:Proto-Oncogene Proteins c-myb; D051788:Myeloid-Lymphoid Leukemia Protein; D050882:CREB-Binding Protein