1my7
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NF-kappaB p65 subunit dimerization domain homodimer N202R mutation
OverviewOverview
IkappaBalpha inhibits transcription factor NF-kappaB activity by specific, binding to NF-kappaB heterodimers composed of p65 and p50 subunits. It, binds with slightly lower affinity to p65 homodimers and with, significantly lower affinity to homodimers of p50. We have employed a, structure-based mutagenesis approach coupled with protein-protein, interaction assays to determine the source of this dimer selectivity, exhibited by IkappaBalpha. Mutation of amino acid residues in IkappaBalpha, that contact NF-kappaB only marginally affects complex binding affinity, indicating a lack of hot spots in NF-kappaB/IkappaBalpha complex, formation. Conversion of the weak binding NF-kappaB p50 homodimer into a, high affinity binding partner of IkappaBalpha requires transfer of both, the NLS polypeptide and amino acid residues Asn202 and Ser203 from the, NF-kappaB p65 subunit. Involvement of Asn202 and Ser203 in complex, formation is surprising as these amino acid residues occupy solvent, exposed positions at a distance of 20A from IkappaBalpha in the crystal, structures. However, the same amino acid residue positions have been, genetically isolated as determinants of binding specificity in a, homologous system in Drosophila. X-ray crystallographic and solvent, accessibility experiments suggest that these solvent-exposed amino acid, residues contribute to NF-kappaB/IkappaBalpha complex formation by, modulating the NF-kappaB p65 subunit NLS polypeptide.
About this StructureAbout this Structure
1MY7 is a Single protein structure of sequence from Mus musculus. Full crystallographic information is available from OCA.
ReferenceReference
Solvent exposed non-contacting amino acids play a critical role in NF-kappaB/IkappaBalpha complex formation., Huxford T, Mishler D, Phelps CB, Huang DB, Sengchanthalangsy LL, Reeves R, Hughes CA, Komives EA, Ghosh G, J Mol Biol. 2002 Dec 6;324(4):587-97. PMID:12460563
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