RGD Reference Report - Functional analysis of the nucleotide binding domain of membrane-associated guanylate kinases. - Rat Genome Database

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Functional analysis of the nucleotide binding domain of membrane-associated guanylate kinases.

Authors: Olsen, O  Bredt, DS 
Citation: Olsen O and Bredt DS, J Biol Chem 2003 Feb 28;278(9):6873-8.
RGD ID: 632536
Pubmed: PMID:12482754   (View Abstract at PubMed)
DOI: DOI:10.1074/jbc.M210165200   (Journal Full-text)

Membrane-associated guanylate kinases (MAGUKs) regulate cellular adhesion and signal transduction at sites of cell-cell contact. MAGUKs are composed of modular protein-protein interaction motifs including L27, PDZ, Src homology (SH) 3, and guanylate kinase domains that aggregate adhesion molecules and receptors. Genetic analyses reveal that lethal mutations of MAGUKs often occur in the guanylate kinase domain, indicating a critical role for this domain. Here, we explored whether GMP binding to the guanylate kinase domain regulates MAGUK function. Surprisingly, and in contrast to previously published studies, we failed to detect GMP binding to the MAGUKs postsynaptic density-95 (PSD-95) and CASK. Two amino acid residues in the GMP binding pocket that differ between MAGUKs and authentic guanylate kinase explain this lack of binding, as swapping these residues largely prevent GMP binding to yeast guanylate kinase. Conversely, these mutations restore GMP binding but not catalytic activity to PSD-95. Protein ligands for the PSD-95 guanylate kinase domain, guanylate kinase-associated protein (GKAP) and MAP1A, appear not to interact with the canonical GMP binding pocket, and GMP binding does not influence the intramolecular SH3/guanylate kinase (GK) interaction within PSD-95. These studies indicate that MAGUK proteins have lost affinity for GMP but may have retained the guanylate kinase structure to accommodate a related regulatory ligand.

Objects referenced in this article
Gene Cask calcium/calmodulin dependent serine protein kinase Rattus norvegicus
Gene Dlg4 discs large MAGUK scaffold protein 4 Rattus norvegicus

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