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Leu628 of the KIX domain of CBP is a key residue for the interaction with the MLL transactivation domain.

ABSTRACT: Physical interaction between the transactivation domain (TAD) of the mixed-lineage leukemia protein (MLL) and the KIX domain of the cyclic-AMP response element binding protein (CREB) binding protein (CBP) is necessary for MLL-mediated transcriptional activation. We show by alanine-scanning mutagenesis that hydrophobic surface residues of KIX, especially L628, are energetically important for binding the MLL TAD. NMR studies of the KIX-L628A mutant suggest that L628 plays a crucial role in conformational transitions at the MLL binding site, necessary for high affinity interactions with MLL. Unexpectedly, MLL also binds to the c-Myb/phosphorylated kinase-inducible domain of CREB (pKID) site of KIX, highlighting the complex nature of interactions involving intrinsically disordered transcriptional activators.

SUBMITTER: Arai M

PROVIDER: S-EPMC2993637 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Leu628 of the KIX domain of CBP is a key residue for the interaction with the MLL transactivation domain.

Arai Munehito M Dyson H Jane HJ Wright Peter E PE

FEBS letters 20101020 22

Physical interaction between the transactivation domain (TAD) of the mixed-lineage leukemia protein (MLL) and the KIX domain of the cyclic-AMP response element binding protein (CREB) binding protein (CBP) is necessary for MLL-mediated transcriptional activation. We show by alanine-scanning mutagenesis that hydrophobic surface residues of KIX, especially L628, are energetically important for binding the MLL TAD. NMR studies of the KIX-L628A mutant suggest that L628 plays a crucial role in conform ...[more]

PMID: 20969867

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| S-EPMC2926944 | biostudies-literature

The CBP KIX domain regulates long-term memory and circadian activity

Project description:Purpose: We investigated the function of the CBP KIX domain in hippocampal memory and gene expression using CBPKIX/KIX mice with mutations that prevent phospho-CREB (Ser133) binding. Method: We performed total RNA sequencing after training for hippocampus-dependent memory from CBP KIX/KIX and WT littermates. Results: Using an unbiased analysis of gene expression after training for hippocampus-dependent memory, we discovered dysregulation of CREB and CLOCK target genes and downregulation of circadian genes in CBPKIX/KIX mice. Conclusion: This study provides insight into the significance of the CBP KIX domain by defining targets of CBP transcriptional co-activation in memory and the role of the CBP KIX domain in vivo on circadian rhythms.

2020-06-03 | GSE151681 | GEO

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