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J Biol Chem, Vol. 275, Issue 12, 8263-8266, March 24, 2000

ACCELERATED PUBLICATION
Stimulus-specific Interaction between Activator-Coactivator Cognates Revealed with a Novel Complex-specific Antiserum^*

Brandee L. Wagner, Anton Bauer^§, Günther Schütz^§, and Marc Montminy^¶

From the  Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037 and ^§ Molecular Biology of the Cell I, Deutsches Krebsforschungszentrum, Im Neuenheimerfeld 280, D-69120 Heidelberg, Germany

A number of second messenger pathways propagate inductive signals via protein-protein interactions that are phosphorylation-dependent. The second messenger, cAMP, for example, promotes cellular gene expression via the protein kinase A-mediated phosphorylation of cAMP-response element-binding protein (CREB) at Ser¹³³, and this modification in turn stimulates the association of CREB with the co-activator, CREB-binding protein (CBP). The solution structure of the CREB·CBP complex, using relevant interaction domains, kinase inducible domain and kinase-induced domain interacting domain, referred to as KID and KIX, respectively, shows that KID undergoes a coil to helix transition, upon binding to KIX, that stabilizes complex formation. Whether such changes occur in the context of the full-length CREB and CBP proteins, however, is unclear. Here we characterize a novel antiserum that specifically binds to the CREB·CBP complex but to neither protein individually. Epitope mapping experiments demonstrate that the CREB·CBP antiserum detects residues in KID that undergo a conformational change upon binding to KIX. The ability of this antiserum to recognize full-length CREB·CBP complexes in a phospho-(Ser¹³³)-dependent manner demonstrates that the structural transition observed with the isolated KID domain also occurs in the context of the full-length CREB protein. To our knowledge, this is the first report documenting formation of endogenous cellular protein-protein complexes in situ.

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^* This work was supported by National Institutes of Health Grants RO1-GM37828 and F32-DK09806.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 619-453-4100 (ext. 1107); Fax: 619-552-1546; E-mail: Montminy@Salk.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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