| Structural highlights
Function
[DLG1_RAT] Essential multidomain scaffolding protein required for normal development (By similarity). Recruits channels, receptors and signaling molecules to discrete plasma membrane domains in polarized cells. Regulates the excitability of cardiac myocytes by modulating the functional expression of Kv4 channels. Functional regulator of Kv1.5 channel (By similarity). May play a role in adherens junction assembly, signal transduction, cell proliferation, synaptogenesis and lymphocyte activation.[1] [2] [3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Synaptic targeting of GluR-A subunit-containing glutamate receptors involves an interaction with synapse-associated protein 97 (SAP97). The C-terminus of GluR-A, which contains a class I PDZ ligand motif (-x-Ser/Thr-x-phi-COOH where phi is an aliphatic amino acid) associates preferentially with the second PDZ domain of SAP97 (SAP97(PDZ2)). To understand the structural basis of this interaction, we have determined the crystal structures of wild-type and a SAP97(PDZ2) variant in complex with an 18-mer C-terminal peptide (residues 890-907) of GluR-A and of two variant PDZ2 domains in unliganded state at 1.8-2.44 A resolutions. SAP97(PDZ2) folds to a compact globular domain comprising six beta-strands and two alpha-helices, a typical architecture for PDZ domains. In the structure of the peptide complex, only the last four C-terminal residues of the GluR-A are visible, and align as an antiparallel beta-strand in the binding groove of SAP97(PDZ2). The free carboxylate group and the aliphatic side chain of the C-terminal leucine (Leu907), and the hydroxyl group of Thr905 of the GluR-A peptide are engaged in essential class I PDZ interactions. Comparison between the free and complexed structures reveals conformational changes which take place upon peptide binding. The betaAlpha-betaBeta loop moves away from the C-terminal end of alphaB leading to a slight opening of the binding groove, which may better accommodate the peptide ligand. The two conformational states are stabilized by alternative hydrogen bond and coulombic interactions of Lys324 in betaAlpha-betaBeta loop with Asp396 or Thr394 in betaBeta. Results of in vitro binding and immunoprecipitation experiments using a PDZ motif-destroying L907A mutation as well as the insertion of an extra alanine residue between the C-terminal Leu907 and the stop codon are also consistent with a 'classical' type I PDZ interaction between SAP97 and GluR-A C-terminus.
Crystal structure of the second PDZ domain of SAP97 in complex with a GluR-A C-terminal peptide.,von Ossowski I, Oksanen E, von Ossowski L, Cai C, Sundberg M, Goldman A, Keinanen K FEBS J. 2006 Nov;273(22):5219-29. Epub 2006 Oct 26. PMID:17069616[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Leonoudakis D, Conti LR, Radeke CM, McGuire LM, Vandenberg CA. A multiprotein trafficking complex composed of SAP97, CASK, Veli, and Mint1 is associated with inward rectifier Kir2 potassium channels. J Biol Chem. 2004 Apr 30;279(18):19051-63. Epub 2004 Feb 11. PMID:14960569 doi:http://dx.doi.org/10.1074/jbc.M400284200
- ↑ Mauceri D, Cattabeni F, Di Luca M, Gardoni F. Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines. J Biol Chem. 2004 May 28;279(22):23813-21. Epub 2004 Mar 24. PMID:15044483 doi:http://dx.doi.org/10.1074/jbc.M402796200
- ↑ Nakagawa T, Futai K, Lashuel HA, Lo I, Okamoto K, Walz T, Hayashi Y, Sheng M. Quaternary structure, protein dynamics, and synaptic function of SAP97 controlled by L27 domain interactions. Neuron. 2004 Oct 28;44(3):453-67. PMID:15504326 doi:http://dx.doi.org/10.1016/j.neuron.2004.10.012
- ↑ El-Haou S, Balse E, Neyroud N, Dilanian G, Gavillet B, Abriel H, Coulombe A, Jeromin A, Hatem SN. Kv4 potassium channels form a tripartite complex with the anchoring protein SAP97 and CaMKII in cardiac myocytes. Circ Res. 2009 Mar 27;104(6):758-69. doi: 10.1161/CIRCRESAHA.108.191007. Epub, 2009 Feb 12. PMID:19213956 doi:10.1161/CIRCRESAHA.108.191007
- ↑ von Ossowski I, Oksanen E, von Ossowski L, Cai C, Sundberg M, Goldman A, Keinanen K. Crystal structure of the second PDZ domain of SAP97 in complex with a GluR-A C-terminal peptide. FEBS J. 2006 Nov;273(22):5219-29. Epub 2006 Oct 26. PMID:17069616 doi:10.1111/j.1742-4658.2006.05521.x
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