Featured System - April 2013
Short description: PDZ domains are specialists in protein recognition, but PSI Biology researchers are revealing their abilities to bind to membranes as well.
Cell signaling requires the coordinated effort of hundreds of proteins. As you can imagine, it helps to have a dedicated infrastructure to organize all of this effort. In our cells, scaffolding proteins play this role, bringing together all the players so that they are in the proper place at the proper time. The scaffolds rely on a series of modular domains, which recognize each of the players and tether them together.
PDZ domains are specialists in recognizing short protein sequences. They are small modular domains, typically with 80-90 amino acids. The protein-recognition site is a groove flanked by a beta sheet on one side and an alpha helix on the other. The beta sheet is perfectly positioned so that a short peptide can zip in, forming a string of hydrogen bonds with the domain. Then, amino acids surrounding the groove can select for the target protein sequence.
The PDZ fold is quite robust and can accommodate many mutations to recognize different peptide sequences. Our own genome contains roughly 250 different PDZ domains, arranged in 150 different proteins. The PDZ domain shown here, solved by PSI researchers at CESG (PDB entry 3lny), shows the interaction between two signaling proteins: the PDZ domain is from PTP1E (in blue) and the short peptide is from RA-GEF2 (in green). Hundreds of other examples are included in the PDB. Often, however, these structures are solved piecemeal: signalling proteins often include several PDZ domains connected by flexible linkers, making them difficult to study.
Recent studies using many experimental and computational techniques, including an elastic network model developed by PSI researchers at MPID, have revealed that some PDZ domains are allosteric proteins that change shape to perform their function. These studies have shown that PDZ domains are highly dynamic, with coordinated motions of individual amino acids that transmit signals from the binding site to other portions of the domain.
PDZ domains are far more scarce in bacteria, but you can find them if you look. They are used, for instance, in huge bacterial proteases. Two examples are shown here. On the left is an aminopeptidase composed of eight identical chains, solved recently by PSI researchers at NESG (PDB entry 4fgm). On the right is DegP, a heat shock protein that acts as a protease and a chaperone (PDB entry 3cs0). In both cases, the PDZ domains (shown in turquoise) form the glue that holds the whole complex together. In the case of DegP, the PDZ domains also interact with unfolded proteins, regulating the action of the protein.
More recently, it has also been discovered that PDZ domains interact with lipids and membranes. The interactions, however, are very different in different types of PDZ domains. PSI researchers at NESG have tested 70 different PDZ domains, and found that over a third of them show significant binding to membranes. Study of the structures of these domains revealed several functional classes. In some cases, the lipid-binding region (shown here in turquoise) is on the opposite side from the peptide-binding groove. In these cases, we might expect that the membrane binding and peptide binding could happen at the same time. Other examples, however, have the lipid-binding amino acids forming part of the alpha helix that flanks the groove. In these cases, the domain probably can't bind to both at the same time, so membrane binding could regulate the binding to peptides, or peptide binding regulate the binding to membranes. To take a closer look at a few of these domains, click on the image for an interactive Jmol.
The JSmol tab below displays an interactive JSmol
PDZ domains fall into several classes when you look at where the lipid-binding sites are located. In SAP102, the lipid-binding amino acids (shown here in turquoise) are on the opposite side from the peptide binding site (the peptide is shown in green). In rhophilin and tamalin, the lipid-binding region is next to the peptide-binding site. Notice also that the lipid-binding amino acids on rhophilin and tamalin are on different places on the PDZ alpha helix. PSI Biology researchers have discovered
Chen, Y. et al. Genome-wide functional annotation of dual-specificity protein- and lipid-binding modules that regulate protein interactions. Mol. Cell 46, 226-237 (2012).
Ivarsson, Y. Plasticity of PDZ domains in ligand recognition and signaling. FEBS Let. 586, 2638-2647 (2012).
Gerek, Z. N. & Ozkan, S. B. Change in allosteric network affects binding affinities of PDZ domains: analysis through perturbation response scanning. PLoS Comp. Biol. 7, e1002154 (2011).
Krojer, T., Sawa, J., Schafer, E., Saibil, H. R., Ehrmann, M. & Clausen, T. Structural basis for the regulated protease and chaperone function of DegP. Nature 453, 885-892 (2008).
Sugi, T., Oyama, T., Muto, T., Nakanishi, S., Morikawa, K. & Jingami, H. Crystal structures of autoinhibitory PDZ domain of tamalin: implications for metabotropic glutamate receptor trafficking regulation. EMBO J. 26, 2192-2205 (2007).