A Specificity Map for the PDZ Domain Family Export

@article{citeulike:3360510, abstract = {PDZ domains are protein–protein interaction modules that recognize specific C-terminal sequences to assemble protein complexes in multicellular organisms. By scanning billions of random peptides, we accurately map binding specificity for approximately half of the over 330 PDZ domains in the human and Caenorhabditis elegans proteomes. The domains recognize features of the last seven ligand positions, and we find 16 distinct specificity classes conserved from worm to human, significantly extending the canonical two-class system based on position −2. Thus, most PDZ domains are not promiscuous, but rather are fine-tuned for specific interactions. Specificity profiling of 91 point mutants of a model PDZ domain reveals that the binding site is highly robust, as all mutants were able to recognize C-terminal peptides. However, many mutations altered specificity for ligand positions both close and far from the mutated position, suggesting that binding specificity can evolve rapidly under mutational pressure. Our specificity map enables the prediction and prioritization of natural protein interactions, which can be used to guide PDZ domain cell biology experiments. Using this approach, we predicted and validated several viral ligands for the PDZ domains of the SCRIB polarity protein. These findings indicate that many viruses produce PDZ ligands that disrupt host protein complexes for their own benefit, and that highly pathogenic strains target PDZ domains involved in cell polarity and growth.}, author = {Tonikian, Raffi and Zhang, Yingnan and Sazinsky, Stephen L. and Currell, Bridget and Yeh, Jung-Hua and Reva, Boris and Held, Heike A. and Appleton, Brent A. and Evangelista, Marie and Wu, Yan and Xin, Xiaofeng and Chan, Andrew C. and Seshagiri, Somasekar and Lasky, Laurence A. and Sander, Chris and Boone, Charles and Bader, Gary D. and Sidhu, Sachdev S.}, citeulike-article-id = {3360510}, citeulike-linkout-0 = {http://dx.doi.org/10.1371/journal.pbio.0060239}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18828675}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18828675}, doi = {10.1371/journal.pbio.0060239}, journal = {PLoS Biology}, keywords = {domain, interaction, protein}, month = {September}, number = {9}, pages = {e239+}, posted-at = {2008-10-20 05:11:28}, priority = {4}, title = {A Specificity Map for the PDZ Domain Family}, url = {http://dx.doi.org/10.1371/journal.pbio.0060239}, volume = {6}, year = {2008} }

TY - JOUR ID - citeulike:3360510 L3 - citeulike-article-id:3360510 N2 - PDZ domains are protein–protein interaction modules that recognize specific C-terminal sequences to assemble protein complexes in multicellular organisms. By scanning billions of random peptides, we accurately map binding specificity for approximately half of the over 330 PDZ domains in the human and Caenorhabditis elegans proteomes. The domains recognize features of the last seven ligand positions, and we find 16 distinct specificity classes conserved from worm to human, significantly extending the canonical two-class system based on position −2. Thus, most PDZ domains are not promiscuous, but rather are fine-tuned for specific interactions. Specificity profiling of 91 point mutants of a model PDZ domain reveals that the binding site is highly robust, as all mutants were able to recognize C-terminal peptides. However, many mutations altered specificity for ligand positions both close and far from the mutated position, suggesting that binding specificity can evolve rapidly under mutational pressure. Our specificity map enables the prediction and prioritization of natural protein interactions, which can be used to guide PDZ domain cell biology experiments. Using this approach, we predicted and validated several viral ligands for the PDZ domains of the SCRIB polarity protein. These findings indicate that many viruses produce PDZ ligands that disrupt host protein complexes for their own benefit, and that highly pathogenic strains target PDZ domains involved in cell polarity and growth. IS - 9 JF - PLoS Biology TI - A Specificity Map for the PDZ Domain Family VL - 6 SP - e239 KW - domain KW - interaction KW - protein AU - Tonikian, Raffi AU - Zhang, Yingnan AU - Sazinsky, Stephen AU - Currell, Bridget AU - Yeh, Jung-Hua AU - Reva, Boris AU - Held, Heike AU - Appleton, Brent AU - Evangelista, Marie AU - Wu, Yan AU - Xin, Xiaofeng AU - Chan, Andrew AU - Seshagiri, Somasekar AU - Lasky, Laurence AU - Sander, Chris AU - Boone, Charles AU - Bader, Gary AU - Sidhu, Sachdev PY - 2008/09/01/ UR - http://dx.doi.org/10.1371/journal.pbio.0060239 ER -