Analysis of an activator:Coactivator complex reveals an essential role for secondary structure in transcriptional activation

David Parker; Ulupi S. Jhala; Ishwar Radhakrishnan; Michael B. Yaffe; Christine Reyes; Andrew I. Shulman; Lewis C. Cantley; Peter E. Wright; Marc Montminy

doi:10.1016/S1097-2765(00)80279-8

Analysis of an activator:Coactivator complex reveals an essential role for secondary structure in transcriptional activation

David Parker, Ulupi S. Jhala, Ishwar Radhakrishnan, Michael B. Yaffe, Christine Reyes, Andrew I. Shulman, Lewis C. Cantley, Peter E. Wright, Marc Montminy^*

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

146 Scopus citations

Abstract

Ser-133 phosphorylation of CREB within the kinase-inducible domain (KID) promotes target gene activation via complex formation with the KIX domain of the coactivator CBP. Concurrent phosphorylation of CREB at Ser-142 inhibits transcriptional induction via an unknown mechanism. Unstructured in the free state, KID folds into a helical structure upon binding to KIX. Using site-directed mutagenesis based on the NMR structure of the KID:KIX complex, we have examined the mechanisms by which Ser-133 and Ser-142 phosphorylation regulate CREB activity. Our results indicate that phospho-Ser-133 stablizes whereas phospho-Ser-142 disrupts secondary structure-mediated interactions between CREB and CBP. Thus, differential phosphorylation of CREB may form the basis by which upstream signals regulate the specificity of target gene activation.

Original language	English (US)
Pages (from-to)	353-359
Number of pages	7
Journal	Molecular cell
Volume	2
Issue number	3
DOIs	https://doi.org/10.1016/S1097-2765(00)80279-8
State	Published - Sep 1998

Funding

We thank Jane Dyson for helpful suggestions, Garry Steil for computer assistance, and Ronald Kahn for providing access to critical equipment. This work was supported by NIH grant RO1-37828.

ASJC Scopus subject areas

Molecular Biology
Cell Biology

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10.1016/S1097-2765(00)80279-8

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@article{045975dcfbe1482d8ab0bc203c7edd9e,

title = "Analysis of an activator:Coactivator complex reveals an essential role for secondary structure in transcriptional activation",

abstract = "Ser-133 phosphorylation of CREB within the kinase-inducible domain (KID) promotes target gene activation via complex formation with the KIX domain of the coactivator CBP. Concurrent phosphorylation of CREB at Ser-142 inhibits transcriptional induction via an unknown mechanism. Unstructured in the free state, KID folds into a helical structure upon binding to KIX. Using site-directed mutagenesis based on the NMR structure of the KID:KIX complex, we have examined the mechanisms by which Ser-133 and Ser-142 phosphorylation regulate CREB activity. Our results indicate that phospho-Ser-133 stablizes whereas phospho-Ser-142 disrupts secondary structure-mediated interactions between CREB and CBP. Thus, differential phosphorylation of CREB may form the basis by which upstream signals regulate the specificity of target gene activation.",

author = "David Parker and Jhala, {Ulupi S.} and Ishwar Radhakrishnan and Yaffe, {Michael B.} and Christine Reyes and Shulman, {Andrew I.} and Cantley, {Lewis C.} and Wright, {Peter E.} and Marc Montminy",

note = "Funding Information: We thank Jane Dyson for helpful suggestions, Garry Steil for computer assistance, and Ronald Kahn for providing access to critical equipment. This work was supported by NIH grant RO1-37828.",

year = "1998",

month = sep,

doi = "10.1016/S1097-2765(00)80279-8",

language = "English (US)",

volume = "2",

pages = "353--359",

journal = "Molecular cell",

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T1 - Analysis of an activator:Coactivator complex reveals an essential role for secondary structure in transcriptional activation

AU - Parker, David

AU - Jhala, Ulupi S.

AU - Radhakrishnan, Ishwar

AU - Yaffe, Michael B.

AU - Reyes, Christine

AU - Shulman, Andrew I.

AU - Cantley, Lewis C.

AU - Wright, Peter E.

AU - Montminy, Marc

N1 - Funding Information: We thank Jane Dyson for helpful suggestions, Garry Steil for computer assistance, and Ronald Kahn for providing access to critical equipment. This work was supported by NIH grant RO1-37828.

PY - 1998/9

Y1 - 1998/9

N2 - Ser-133 phosphorylation of CREB within the kinase-inducible domain (KID) promotes target gene activation via complex formation with the KIX domain of the coactivator CBP. Concurrent phosphorylation of CREB at Ser-142 inhibits transcriptional induction via an unknown mechanism. Unstructured in the free state, KID folds into a helical structure upon binding to KIX. Using site-directed mutagenesis based on the NMR structure of the KID:KIX complex, we have examined the mechanisms by which Ser-133 and Ser-142 phosphorylation regulate CREB activity. Our results indicate that phospho-Ser-133 stablizes whereas phospho-Ser-142 disrupts secondary structure-mediated interactions between CREB and CBP. Thus, differential phosphorylation of CREB may form the basis by which upstream signals regulate the specificity of target gene activation.

AB - Ser-133 phosphorylation of CREB within the kinase-inducible domain (KID) promotes target gene activation via complex formation with the KIX domain of the coactivator CBP. Concurrent phosphorylation of CREB at Ser-142 inhibits transcriptional induction via an unknown mechanism. Unstructured in the free state, KID folds into a helical structure upon binding to KIX. Using site-directed mutagenesis based on the NMR structure of the KID:KIX complex, we have examined the mechanisms by which Ser-133 and Ser-142 phosphorylation regulate CREB activity. Our results indicate that phospho-Ser-133 stablizes whereas phospho-Ser-142 disrupts secondary structure-mediated interactions between CREB and CBP. Thus, differential phosphorylation of CREB may form the basis by which upstream signals regulate the specificity of target gene activation.

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Analysis of an activator:Coactivator complex reveals an essential role for secondary structure in transcriptional activation

Abstract

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ASJC Scopus subject areas

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