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Cited by 476Protein Structure and DynamicsChemical Synthesis and AnalysisProtein Kinase Regulation and GTPase Signaling

A Specificity Map for the PDZ Domain Family

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Tonikian, Raffi, Zhang, Yingnan, Sazinsky, Stephen L, Currell, Bridget, Yeh, Jung-Hua, Reva, Boris, Held, Heike A, Appleton, Brent A +10 more·2008·PLoS Biology
DOI 10.1371/journal.pbio.0060239PMC PMC2553845
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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.

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  • The DOCK4 C terminus (1962KVSQL1966) matches the [RK]-x-[ST] consensus pattern present in a class of known PDZ ligands.

    “Although the exact role of individual amino acids within this motif has not been experimentally addressed to date, the DOCK4 C terminus (1962KVSQL1966) matches the [RK]-x-[ST] consensus pattern present in a class of known PDZ ligands (Tonikian et al. 2008).”

    From Heterozygous loss-of-function variants in DOCK4 cause neurodevelopmental delay and microcephaly (2024) · cites this paper as Tonikian et al. 2008

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Authors
Tonikian, R., Zhang, Y., Sazinsky, S. L., Currell, B., Yeh, J.-H., Reva, B., Held, H. A., Appleton, B. A., Evangelista, M., Wu, Y., Xin, X., Chan, A. C., Seshagiri, S., Lasky, L. A., Sander, C., Boone, C., Bader, G. D., & Sidhu, S. S.
Affiliations
  • University of Toronto (CA)
  • Genentech (US)
  • Massachusetts Institute of Technology (US)
  • Memorial Sloan Kettering Cancer Center (US)
Corresponding author
  • Boone, Charles
  • Bader, Gary D
  • Sidhu, Sachdev S
ORCID
Venue
PLoS Biology
Publisher
Public Library of Science (PLoS)
Published
2008-09-30
Volume
6
Issue
9
Pages
e239
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.0060239
PMC
PMC2553845
OpenAlex
W2074570440
Cited by
476
References
3
Citations by year
2026: 9 · 2025: 13 · 2024: 12 · 2023: 22 · 2022: 18 · 2021: 30 · 2020: 17 · 2019: 20 · 2018: 21 · 2017: 26 · 2016: 23 · 2015: 26 · 2014: 35 · 2013: 31 · 2012: 50
FWCI
16.89
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Funders
  • Genentech
  • National Cancer Institute
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
PDZ domain, protein-protein interaction, binding specificity, point mutants, SCRIB, cell polarity, Caenorhabditis elegans, human proteome, protein complex formation
MeSH terms
Amino Acid Sequence, Animals, Binding Sites, Humans, Membrane Proteins, Models, Molecular, Molecular Sequence Data, Mutation, Peptides, Phylogeny, Viral Proteins, Protein Structure, Secondary, Proteome, Tumor Suppressor Proteins, Caenorhabditis elegans Proteins, PDZ Domains

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