Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

Science 317 (5836): 364-369

Copyright © 2007 by the American Association for the Advancement of Science

PDZ Domain Binding Selectivity Is Optimized Across the Mouse Proteome

Michael A. Stiffler,1* Jiunn R. Chen,2* Viara P. Grantcharova,1{dagger} Ying Lei,1 Daniel Fuchs,1 John E. Allen,1 Lioudmila A. Zaslavskaia,1{ddagger} Gavin MacBeath1§

Abstract: PDZ domains have long been thought to cluster into discrete functional classes defined by their peptide-binding preferences. We used protein microarrays and quantitative fluorescence polarization to characterize the binding selectivity of 157 mouse PDZ domains with respect to 217 genome-encoded peptides. We then trained a multidomain selectivity model to predict PDZ domain–peptide interactions across the mouse proteome with an accuracy that exceeds many large-scale, experimental investigations of protein-protein interactions. Contrary to the current paradigm, PDZ domains do not fall into discrete classes; instead, they are evenly distributed throughout selectivity space, which suggests that they have been optimized across the proteome to minimize cross-reactivity. We predict that focusing on families of interaction domains, which facilitates the integration of experimentation and modeling, will play an increasingly important role in future investigations of protein function.

1 Department of Chemistry and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.
2 Department of Molecular and Cellular Biology, Harvard University, 12 Oxford Street, Cambridge, MA 02138, USA.

* These authors contributed equally to this work.

{dagger} Present address: Merrimack Pharmaceuticals, 1 Kendall Square, Building 700, Cambridge, MA 02139, USA.

{ddagger} Present address: Tepnel Lifecodes Corporation, 550 West Avenue, Stamford, CT 06902, USA.

§ To whom correspondence should be addressed. E-mail: macbeath{at}chemistry.harvard.edu

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Claudins and the Modulation of Tight Junction Permeability.
D. Gunzel and A. S. L. Yu (2013)
Physiol Rev 93, 525-569
   Abstract »    Full Text »    PDF »
Stereochemical Determinants of C-terminal Specificity in PDZ Peptide-binding Domains: A NOVEL CONTRIBUTION OF THE CARBOXYLATE-BINDING LOOP.
J. F. Amacher, P. R. Cushing, C. D. Bahl, T. Beck, and D. R. Madden (2013)
J. Biol. Chem. 288, 5114-5126
   Abstract »    Full Text »    PDF »
Coiled-coil networking shapes cell molecular machinery.
Y. Wang, X. Zhang, H. Zhang, Y. Lu, H. Huang, X. Dong, J. Chen, J. Dong, X. Yang, H. Hang, et al. (2012)
Mol. Biol. Cell 23, 3911-3922
   Abstract »    Full Text »    PDF »
Superbinder SH2 Domains Act as Antagonists of Cell Signaling.
T. Kaneko, H. Huang, X. Cao, X. Li, C. Li, C. Voss, S. S. Sidhu, and S. S. C. Li (2012)
Science Signaling 5, ra68
   Abstract »    Full Text »    PDF »
Interference with the PTEN-MAST2 Interaction by a Viral Protein Leads to Cellular Relocalization of PTEN.
E. Terrien, A. Chaffotte, M. Lafage, Z. Khan, C. Prehaud, F. Cordier, C. Simenel, M. Delepierre, H. Buc, M. Lafon, et al. (2012)
Science Signaling 5, ra58
   Abstract »    Full Text »    PDF »
Dynamic reciprocity of sodium and potassium channel expression in a macromolecular complex controls cardiac excitability and arrhythmia.
M. L. Milstein, H. Musa, D. P. Balbuena, J. M. B. Anumonwo, D. S. Auerbach, P. B. Furspan, L. Hou, B. Hu, S. M. Schumacher, R. Vaidyanathan, et al. (2012)
PNAS 109, E2134-E2143
   Abstract »    Full Text »    PDF »
Dynamic of Ion Channel Expression at the Plasma Membrane of Cardiomyocytes.
E. Balse, D. F. Steele, H. Abriel, A. Coulombe, D. Fedida, and S. N. Hatem (2012)
Physiol Rev 92, 1317-1358
   Abstract »    Full Text »    PDF »
PDZ Domain-containing 1 (PDZK1) Protein Regulates Phospholipase C-{beta}3 (PLC-{beta}3)-specific Activation of Somatostatin by Forming a Ternary Complex with PLC-{beta}3 and Somatostatin Receptors.
J. K. Kim, O. Kwon, J. Kim, E.-K. Kim, H. K. Park, J. E. Lee, K. L. Kim, J. W. Choi, S. Lim, H. Seok, et al. (2012)
J. Biol. Chem. 287, 21012-21024
   Abstract »    Full Text »    PDF »
MUSI: an integrated system for identifying multiple specificity from very large peptide or nucleic acid data sets.
T. Kim, M. S. Tyndel, H. Huang, S. S. Sidhu, G. D. Bader, D. Gfeller, and P. M. Kim (2012)
Nucleic Acids Res. 40, e47
   Abstract »    Full Text »    PDF »
Dynamic Na+-H+ Exchanger Regulatory Factor-1 Association and Dissociation Regulate Parathyroid Hormone Receptor Trafficking at Membrane Microdomains.
J. A. Ardura, B. Wang, S. C. Watkins, J.-P. Vilardaga, and P. A. Friedman (2011)
J. Biol. Chem. 286, 35020-35029
   Abstract »    Full Text »    PDF »
Sequence-specific Long Range Networks in PSD-95/Discs Large/ZO-1 (PDZ) Domains Tune Their Binding Selectivity.
S. Gianni, S. R. Haq, L. C. Montemiglio, M. C. Jurgens, A. Engstrom, C. N. Chi, M. Brunori, and P. Jemth (2011)
J. Biol. Chem. 286, 27167-27175
   Abstract »    Full Text »    PDF »
Mechanism underlying selective regulation of G protein-gated inwardly rectifying potassium channels by the psychostimulant-sensitive sorting nexin 27.
B. Balana, I. Maslennikov, W. Kwiatkowski, K. M. Stern, L. Bahima, S. Choe, and P. A. Slesinger (2011)
PNAS 108, 5831-5836
   Abstract »    Full Text »    PDF »
SAP97 and Dystrophin Macromolecular Complexes Determine Two Pools of Cardiac Sodium Channels Nav1.5 in Cardiomyocytes.
S. Petitprez, A.-F. Zmoos, J. Ogrodnik, E. Balse, N. Raad, S. El-Haou, M. Albesa, P. Bittihn, S. Luther, S. E. Lehnart, et al. (2011)
Circ. Res. 108, 294-304
   Abstract »    Full Text »    PDF »
A regression framework incorporating quantitative and negative interaction data improves quantitative prediction of PDZ domain-peptide interaction from primary sequence.
X. Shao, C. S. H. Tan, C. Voss, S. S. C. Li, N. Deng, and G. D. Bader (2011)
Bioinformatics 27, 383-390
   Abstract »    Full Text »    PDF »
Identification of Transmembrane Protein 88 (TMEM88) as a Dishevelled-binding Protein.
H.-J. Lee, D. Finkelstein, X. Li, D. Wu, D.-L. Shi, and J. J. Zheng (2010)
J. Biol. Chem. 285, 41549-41556
   Abstract »    Full Text »    PDF »
SH2 Domains Recognize Contextual Peptide Sequence Information to Determine Selectivity.
B. A. Liu, K. Jablonowski, E. E. Shah, B. W. Engelmann, R. B. Jones, and P. D. Nash (2010)
Mol. Cell. Proteomics 9, 2391-2404
   Abstract »    Full Text »    PDF »
Polycystin-2 Activity Is Controlled by Transcriptional Coactivator with PDZ Binding Motif and PALS1-associated Tight Junction Protein.
K. Duning, D. Rosenbusch, M. A. Schluter, Y. Tian, K. Kunzelmann, N. Meyer, U. Schulze, A. Markoff, H. Pavenstadt, and T. Weide (2010)
J. Biol. Chem. 285, 33584-33588
   Abstract »    Full Text »    PDF »
Specificity in Computational Protein Design.
J. J. Havranek (2010)
J. Biol. Chem. 285, 31095-31099
   Abstract »    Full Text »    PDF »
Prediction of protease substrates using sequence and structure features.
D. T. Barkan, D. R. Hostetter, S. Mahrus, U. Pieper, J. A. Wells, C. S. Craik, and A. Sali (2010)
Bioinformatics 26, 1714-1722
   Abstract »    Full Text »    PDF »
Phylogenetic Analysis of Gene Structure and Alternative Splicing in {alpha}-Actinins.
M. Lek, D. G. MacArthur, N. Yang, and K. N. North (2010)
Mol. Biol. Evol. 27, 773-780
   Abstract »    Full Text »    PDF »
The structure of the harmonin/sans complex reveals an unexpected interaction mode of the two Usher syndrome proteins.
J. Yan, L. Pan, X. Chen, L. Wu, and M. Zhang (2010)
PNAS 107, 4040-4045
   Abstract »    Full Text »    PDF »
PDZ-domain-directed basolateral targeting of the peripheral membrane protein FRMPD2 in epithelial cells.
N. Stenzel, C. P. Fetzer, R. Heumann, and K. S. Erdmann (2009)
J. Cell Sci. 122, 3374-3384
   Abstract »    Full Text »    PDF »
Cell Polarity Factor Par3 Binds SPTLC1 and Modulates Monocyte Serine Palmitoyltransferase Activity and Chemotaxis.
N. Tamehiro, Z. Mujawar, S. Zhou, D. Z. Zhuang, T. Hornemann, A. von Eckardstein, and M. L. Fitzgerald (2009)
J. Biol. Chem. 284, 24881-24890
   Abstract »    Full Text »    PDF »
Rapid Evolution of Functional Complexity in a Domain Family.
A. Ernst, S. L. Sazinsky, S. Hui, B. Currell, M. Dharsee, S. Seshagiri, G. D. Bader, and S. S. Sidhu (2009)
Science Signaling 2, ra50
   Abstract »    Full Text »    PDF »
Pin1 Catalyzes Conformational Changes of Thr-187 in p27Kip1 and Mediates Its Stability through a Polyubiquitination Process.
W. Zhou, Q. Yang, C. B. Low, B. C. Karthik, Y. Wang, A. Ryo, S. Q. Yao, D. Yang, and Y.-C. Liou (2009)
J. Biol. Chem. 284, 23980-23988
   Abstract »    Full Text »    PDF »
The Protein Scaffold NHERF-1 Controls the Amplitude and Duration of Localized Protein Kinase D Activity.
M. T. Kunkel, E. L. Garcia, T. Kajimoto, R. A. Hall, and A. C. Newton (2009)
J. Biol. Chem. 284, 24653-24661
   Abstract »    Full Text »    PDF »
Using genome-wide measurements for computational prediction of SH2-peptide interactions.
Z. Wunderlich and L. A. Mirny (2009)
Nucleic Acids Res. 37, 4629-4641
   Abstract »    Full Text »    PDF »
Characterization of Domain-Peptide Interaction Interface: A Generic Structure-based Model to Decipher the Binding Specificity of SH3 Domains.
T. Hou, Z. Xu, W. Zhang, W. A. McLaughlin, D. A. Case, Y. Xu, and W. Wang (2009)
Mol. Cell. Proteomics 8, 639-649
   Abstract »    Full Text »    PDF »
Kv4 Potassium Channels Form a Tripartite Complex With the Anchoring Protein SAP97 and CaMKII in Cardiac Myocytes.
S. El-Haou, E. Balse, N. Neyroud, G. Dilanian, B. Gavillet, H. Abriel, A. Coulombe, A. Jeromin, and S. N. Hatem (2009)
Circ. Res. 104, 758-769
   Abstract »    Full Text »    PDF »
How Perfect Can Protein Interactomes Be?.
E. D. Levy, C. R. Landry, and S. W. Michnick (2009)
Science Signaling 2, pe11
   Abstract »    Full Text »    PDF »
The use of amphipols as universal molecular adapters to immobilize membrane proteins onto solid supports.
D. Charvolin, J.-B. Perez, F. Rouviere, F. Giusti, P. Bazzacco, A. Abdine, F. Rappaport, K. L. Martinez, and J.-L. Popot (2009)
PNAS 106, 405-410
   Abstract »    Full Text »    PDF »
A Pair of Circularly Permutated PDZ Domains Control RseP, the S2P Family Intramembrane Protease of Escherichia coli.
K. Inaba, M. Suzuki, K.-i. Maegawa, S. Akiyama, K. Ito, and Y. Akiyama (2008)
J. Biol. Chem. 283, 35042-35052
   Abstract »    Full Text »    PDF »
The PDZ Protein Mupp1 Promotes Gi Coupling and Signaling of the Mt1 Melatonin Receptor.
J.-L. Guillaume, A. M. Daulat, P. Maurice, A. Levoye, M. Migaud, L. Brydon, B. Malpaux, C. Borg-Capra, and R. Jockers (2008)
J. Biol. Chem. 283, 16762-16771
   Abstract »    Full Text »    PDF »
The anchoring protein SAP97 retains Kv1.5 channels in the plasma membrane of cardiac myocytes.
J. Abi-Char, S. El-Haou, E. Balse, N. Neyroud, R. Vranckx, A. Coulombe, and S. N. Hatem (2008)
Am J Physiol Heart Circ Physiol 294, H1851-H1861
   Abstract »    Full Text »    PDF »
Improving yeast two-hybrid screening systems.
M. Koegl and P. Uetz (2008)
Briefings in Functional Genomics
   Abstract »    Full Text »    PDF »
Domain Swapping within PDZ2 Is Responsible for Dimerization of ZO Proteins.
A. S. Fanning, M. F. Lye, J. M. Anderson, and A. Lavie (2007)
J. Biol. Chem. 282, 37710-37716
   Abstract »    Full Text »    PDF »
Putting the glue in glia: Necls mediate Schwann cell axon adhesion.
J. R. Perlin and W. S. Talbot (2007)
J. Cell Biol. 178, 721-723
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882