{PDOC50106} {PS50106; PDZ} {BEGIN} ********************** * PDZ domain profile * ********************** PDZ domains (also called Discs-large homologous regions (DHR) or GLGF) are conserved structural elements of 80 to 100 amino acids that were originally identified in the post-synaptic density protein PSD-95, the Drosophila tumor suppressor discs-large, and the tight-junction protein ZO-1. PDZ domains occur as single or, more frequently, as multiple tandemly repeated copies in a large and diverse set of proteins from all eukaryotes [1,2]. The presence of one or two copies of PDZ domains in some bacteria may be explained by horizontal gene transfer [3]. Eukaryotic PDZ domains are multifunctional protein-protein interaction modules that are involved in the clustering of signaling molecules and play important role in organizing protein networks on membranes. In many cases, PDZ domains bind to a signature motif ([FYST]-X-[FVA]) occurring at the very C-terminus of target proteins. PDZ domains are also able to form heterodimers, and to interact with internal peptide fragments of target proteins [1,2,4]. It has been proposed that bacterial PDZ domains also possess C-terminal polypeptide binding functions [3]. PDZ domains are compact globular domains that were originally called GLGF as Gly-Leu-Gly-Phe is a relatively conserved element of their sequences [1]. Resolution of crystal and solution structures of PDZ domains with and without ligands has revealed that the PDZ domain contains six beta-strands and two alpha-helices [5,6,7,8]. The C-terminal motif of target proteins has been shown to bind in an anti-parallel fashion to a groove formed by the principal alpha-helix and the second beta-strand of the PDZ domains [5,8]. The binding site involved in the heterodimerization of some PDZ domains is situated opposite this canonical peptide binding groove. It is an about 30 residue C- terminal extension of the PDZ domain, which forms a beta-hairpin finger. The first strand of the beta-hairpin finger mimics a canonical C-terminal peptide ligand, inserting into the peptide binding groove of the PDZ domain from the partner protein [7,8]. It has been proposed that PDZ domains may bind in a general fashion to non-terminal sequences, possibly those with beta-finger- type structures, regardless of whether or not they are found downstream of other PDZ domains [9]. Some proteins known to contain a PDZ domain are listed below: - Eukaryotic membrane associated guanylate kinases (MAGUKs). - Mammalian amyloid beta A4 precursor protein-binding family A proteins, putative function in synaptic vesicle exocytosis by binding to Munc18-1, an essential component of the synaptic vesicle exocytotic machinery. - Mammalian neuronal nitric oxide synthase (nNOS). - Interleukin-16, the only known secreted member of the PDZ protein family. - Vertebrate LIM-kinases (LIMK), which display serine/threonine-specific phosphorylation of myelin basic protein and histone in vitro. - Drosophila and vertebrate dishevelled (Dsh and Dvl), proteins that play a key role in the transduction of the Wg/Wnt signal from the cell surface to the nucleus. - Drosophila InaD, a photoreceptor scaffolding protein that assembles multiple signal transducing proteins at the membrane via its 5 PDZ domains. - Bacillus subtilis stage IV sporulation B protein (spOIVB). - Bacterial gspC proteins, involved in protein export via type II secretion systems. - Bacterial periplasmic serine proteases high-temperature requirement A (htrA) and tail-specific protease (tsp). - Escherichia coli and Haemophilus influenzae hypothetical protein YaeL, probably associated with the cytoplasmic membrane. A profile was developed that covers the minimal PDZ domain and thus lacks about 30 C-terminal residues (which form the beta finger involved in PDZ-PDZ interactions). -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: December 2001 / First entry. [ 1] Ponting C.P., Phillips C., Davies K.E., Blake D.J. "PDZ domains: targeting signalling molecules to sub-membranous sites." BioEssays 19:469-479(1997). PubMed=9204764 [ 2] Ranganathan R., Ross E.M. "PDZ domain proteins: scaffolds for signaling complexes." Curr. Biol. 7:R770-R773(1997). PubMed=9382826 [ 3] Ponting C.P. "Evidence for PDZ domains in bacteria, yeast, and plants." Protein Sci. 6:464-468(1997). PubMed=9041651 [ 4] Fuh G., Pisabarro M.T., Li Y., Quan C., Lasky L.A., Sidhu S.S. "Analysis of PDZ domain-ligand interactions using carboxyl-terminal phage display." J. Biol. Chem. 275:21486-21491(2000). PubMed=10887205; DOI=275/28/21486 [ 5] Doyle D.A., Lee A., Lewis J., Kim E., Sheng M., MacKinnon R. "Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ." Cell 85:1067-1076(1996). PubMed=8674113 [ 6] Morais Cabral J.H., Petosa C., Sutcliffe M.J., Raza S., Byron O., Poy F., Marfatia S.M., Chishti A.H., Liddington R.C. Nature 382:649-652(1996). [ 7] Hillier B.J., Christopherson K.S., Prehoda K.E., Bredt D.S., Lim W.A. "Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex." Science 284:812-815(1999). PubMed=10221915 [ 8] Tochio H., Zhang Q., Mandal P., Li M., Zhang M. "Solution structure of the extended neuronal nitric oxide synthase PDZ domain complexed with an associated peptide." Nat. Struct. Biol. 6:417-421(1999). PubMed=10331866; DOI=10.1038/8216 [ 9] Oschkinat H. "A new type of PDZ domain recognition." Nat. Struct. Biol. 6:408-410(1999). PubMed=10331862; DOI=10.1038/8203 -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}