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Papers In Press, published online ahead of print December 27, 2000
J. Biol. Chem, 10.1074/jbc.M010263200
Submitted on November 10, 2000
Revised on December 19, 2000
Accepted on December 27, 2000
Vollum Institute, Oregon Health Sciences University, Portland, OR 97201
Corresponding Author: goodmanr{at}ohsu.edu
Recent determination of the CREB bZIP:consensus CRE crystal structure revealed key dimerization and DNA binding features that are conserved among members of the CREB/CREM/ATF-1 family of transcription factors. Dimerization appeared to be mediated by a Tyr307:Glu312 interhelical hydrogen bond and a Glu319:Arg314 electrostatic interaction. An unexpected hexahydrated Mg2+ ion was centered above the CRE in the dimer cavity. In the present study, we related these features to CREB dimerization and DNA binding. A Tyr307Phe substitution reduced dimer stability and DNA binding affinity, whereas a Tyr307Arg mutation produced a stabilizing effect. Mutation of Glu 319 to Ala or Lys attenuated dimerization and DNA binding. Mg2+ ions enhanced the binding affinity of wild-type CREB to the palindromic CRE by approximately 20-fold, but did not do so for divergent CREs. Similarly, mutation of Lys 304, which mediates the CREB interaction with the hydrated Mg2+, blocked CREB binding to the palindromic but not the variant CRE sequences. The distinct binding characteristics of the Lys304Ala mutants to the consensus and variant CRE sequences indicate that CREB binding to these elements is differentially regulated by Mg2+ ions. We suggest that CREB binds the consensus and variant CRE sequences through fundamentally distinct mechanisms.
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