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Mechanism and role of PDZ domains in signaling complex assembly

Baruch Z. Harris and Wendell A. Lim*

Department of Cellular and Molecular Pharmacology, University of California San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143-0450, USA



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  		Fig. 1. Structure of the PDZ domain and mechanism of peptide recognition. (A) Ribbon diagram of PSD-95 PDZ domain 3 (residues 306-394, shown in red) with a bound peptide (NH2-KQTSV-COOH, shown in blue). Names of ß-strands and {alpha}-helices are indicated. The side chains of the peptide P0 residue (valine) and P-2 residue (threonine) are shown in stick form, as is the terminal carboxylate. (B) Diagram of the peptide-binding pocket. Residues in the PDZ-domain-binding pocket are shown in black; the peptide is shown in blue. Hydrogen bonds are drawn as red dotted lines, and hydrophobic packing is indicated by green arcs. (C) Solvent-accessible surface representation of the structure shown in (A) (probe radius=1.4 Å). The peptide is drawn as in A, and key binding pockets are indicated by circles (Doyle et al., 1996).

 


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  		Fig. 2. The same PDZ domain can recognize two structurally distinct ligands. The {alpha}1-syntrophin PDZ domain is shown as a gray solvent-accessible surface. (A) The ligand is canonical peptide NH2-VKESLV-COOH, shown as a red tube (Schultz et al., 1998). (B) The ligand is the nNOS PDZ domain with its distinctive ß-finger motif (indicated), shown as a red ribbon diagram. The internal peptide motif that mimics a C-terminal peptide is indicated (Hillier et al., 1999).

 


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  		Fig. 3. Structures of related ‘PDZ-like’ domains. Proteins are shown in ribbon form; ß-strands are shown in turquoise, and {alpha}-helices are shown in red. (A) A canonical metazoan PDZ domain exemplified by the third PDZ domain of PSD-95 (residues 306-394), shown with a bound peptide (dark blue) as in Fig. 1 (Doyle et al., 1996). (B) Interleukin 16 (IL-16), residues 25-119. Trp-99, shown in stick form, occludes the normal PDZ peptide-binding site (Mühlhahn et al., 1998). (C) The photosystem D1 protease (residues 157-249) from Scenedesmus obliquus. The structure is circularly permuted relative to the structures in (A) and (B), but the fold is essentially the same (Liao et al., 2000). Note that, in all structures, the N- and C-termini of the domains are close together.

 


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  		Fig. 4. Examples of higher-order organization of PDZ domains found in signaling proteins. Proteins are indicated in black lines scaled to the length of the primary sequence of the protein; PDZ domains are shown in yellow. Other domains are indicated as abbreviations (from SMART) (Schultz et al., 2000) as follows: SH3, Src-homology 3 domain; GuK, guanylate-kinase-like domain; LIM, zinc-binding domain present in Lin-11, Isl-1, Mec-3; PH, pleckstrin-homology domain; RBD, Raf-like Ras-binding domain; RhoGEF, Rho-like GTP-exchange factor; DAX, Dishevelled- and axin-homology domain; DEP, Dishevelled-, Egl-10- and pleckstrin-homology domain.

 


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  		Fig. 5. PDZ domains co-occur more frequently than comparable signaling domains in the human genome. Distributions of multiple signaling domains in a single ORF as predicted by SMART (Schultz et al., 2000) are shown for SH2, SH3 and PDZ domains. ORFs are separated according to those that contain 1 (gray), 2 (purple), 3-5 (blue) and >5 (red) of a single type of domain in the same polypeptide. PDZ domains are much more likely to occur in multiple copies.

 


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  		Fig. 6. INAD coordinates the Drosophila melanogaster phototransduction cascade. (A) Domain structure of INAD; arrows indicate putative protein-protein interactions. (B) Diagram of the Drosophila phototransduction cascade. The full photoreceptor cell is at top left. At top right, a section of the cell is expanded to show the stacking of rhabdomeres. Below, a schematic representation of the signaling pathway coordinated by INAD. INAD is indicated by five yellow PDZ domains connected by a black line. Abbreviations for proteins that form the phototransduction signaling cascade are as follows: TRP/TRPL, transient-receptor-potential-type Ca2+ channels; G{alpha}q, the G{alpha} subunit of the heterotrimeric G protein involved in the Drosophila phototransduction pathway; PLC, phospholipase Cß; PKC, eye-specific protein kinase C; CaM, calmodulin.

 


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  		Fig. 7. LIN-2, LIN-7 and LIN-10 form a conserved PDZ-mediated transport complex in polarized cells. (A) Diagram of the three proteins, showing their interactions with each other, which leave all three PDZ domains free to bind ligands. (B ) Diagram of C. elegans vulval precursor epithelial cells. LIN-2, LIN-7 and LIN-10 form a tripartite complex that is essential for targeting of the tyrosine kinase receptor LET-23; proper localization of LET-23 is required for it to detect its ligand, LIN-3, which is present only on the basolateral side (Kaech et al., 1998; Simske et al., 1996). (C) Schematic diagram of the mammalian neuron, showing transport along microtubules of vesicle containing NMDA receptors. The mammalian homolog of LIN-7 (MALS) binds to the C-terminal tail of NMDA receptor subunit 2B, whereas the LIN-10 homolog (MINT1) binds the kinesin superfamily motor protein KIF17. CASK, the LIN-2 homolog, links MALS and MINT1 together. The entire complex, including NMDA-receptor-containing vesicles, is proposed to move along microtubules to the neuronal dendrite (Setou et al., 2000). This complex thus forms a transport system that targets proteins to their appropriate subcellular locations.

 

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