Abstract
BackgroundThe interactions between PDZ (PSD-95, Dlg, ZO-1) domains and PDZ-binding motifs play central roles in signal transductions within cells. Proteins with PDZ domains bind to PDZ-binding motifs almost exclusively when the motifs are located at the carboxyl (C-) terminal ends of their binding partners. However, it remains little explored whether PDZ-binding motifs show any preferential location at the C-terminal ends of proteins, at genome-level.ResultsHere, we examined the distribution of the type-I (x-x-S/T-x-I/L/V) or type-II (x-x-V-x-I/V) PDZ-binding motifs in proteins encoded in the genomes of five different species (human, mouse, zebrafish, fruit fly and nematode). We first established that these PDZ-binding motifs are indeed preferentially present at their C-terminal ends. Moreover, we found specific amino acid (AA) bias for the 'x' positions in the motifs at the C-terminal ends. In general, hydrophilic AAs were favored. Our genomics-based findings confirm and largely extend the results of previous interaction-based studies, allowing us to propose refined consensus sequences for all of the examined PDZ-binding motifs. An ontological analysis revealed that the refined motifs are functionally relevant since a large fraction of the proteins bearing the motif appear to be involved in signal transduction. Furthermore, co-precipitation experiments confirmed two new protein interactions predicted by our genomics-based approach. Finally, we show that influenza virus pathogenicity can be correlated with PDZ-binding motif, with high-virulence viral proteins bearing a refined PDZ-binding motif.ConclusionsOur refined definition of PDZ-binding motifs should provide important clues for identifying functional PDZ-binding motifs and proteins involved in signal transduction.
Highlights
The interactions between PDZ (PSD-95, ZO-1)-binding motif (Dlg), ZO-1) domains and PDZ-binding motifs play central roles in signal transductions within cells
PB motifs are currently categorized into at least three major types on the basis of two amino acid (AA) located at positions 0 and -2 (Figure 1, upper panel), both being essential for binding to PDZ domains [11,13,14,15]
Our pilot survey revealed that 84.6%, 82.7%, 80.7%, 77.4% and 79.7% of genes in the genome of the respective species listed above encodes proteins possessing at least one PB motif at any C0-C50 positions, confirming that the PB motifs are highly common AA sequence
Summary
The interactions between PDZ (PSD-95, Dlg, ZO-1) domains and PDZ-binding motifs play central roles in signal transductions within cells. Proteins with PDZ domains bind to PDZ-binding motifs almost exclusively when the motifs are located at the carboxyl (C-) terminal ends of their binding partners. The proteins that contain PDZ domain(s), often called PDZ proteins, play pivotal roles in dynamically organizing molecular architectures at specific intracellular regions in differentiating and differentiated cells [1,2]. Membrane proteins such as cell adhesion molecules, receptors, and channels form functional clusters within selective subcellular regions by binding to PDZ domains [2,3,4,5]. The type-I PB motif has the form S/T-x-I/L/
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