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      Affinity Enhancement by Ligand Clustering Effect Inspired by Peptide Dendrimers−Shank PDZ Proteins Interactions

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          Abstract

          High-affinity binders are desirable tools to probe the function that specific protein−protein interactions play in cell. In the process of seeking a general strategy to design high-affinity binders, we found a clue from the βPIX (p21-activated kinase interacting exchange factor)−Shank PDZ interaction in synaptic assembly: three PDZ-binding sites are clustered by a parallel coiled-coil trimer but bind to Shank PDZ protein with 1:1 stoichiometry (1 trimer/1 PDZ). Inspired by this architecture, we proposed that peptide dendrimer, mimicking the ligand clustering in βPIX, will also show enhanced binding affinity, yet with 1:1 stoichiometry. This postulation has been proven here, as we synthesized a set of monomeric, dimeric and trimeric peptides and measured their binding affinity and stoichiometry with Shank PDZ domains by isothermal titration calorimetry, native mass spectrometry and surface plasmon resonance. This affinity enhancement, best explained by proximity effect, will be useful to guide the design of high-affinity blockers for protein−protein interactions.

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          Modeling autism by SHANK gene mutations in mice.

          Yong-Hui Jiang, Michael Ehlers (2013)
          Shank family proteins (Shank1, Shank2, and Shank3) are synaptic scaffolding proteins that organize an extensive protein complex at the postsynaptic density (PSD) of excitatory glutamatergic synapses. Recent human genetic studies indicate that SHANK family genes (SHANK1, SHANK2, and SHANK3) are causative genes for idiopathic autism spectrum disorders (ASD). Neurobiological studies of Shank mutations in mice support a general hypothesis of synaptic dysfunction in the pathophysiology of ASD. However, the molecular diversity of SHANK family gene products, as well as the heterogeneity in human and mouse phenotypes, pose challenges to modeling human SHANK mutations. Here, we review the molecular genetics of SHANK mutations in human ASD and discuss recent findings where such mutations have been modeled in mice. Conserved features of synaptic dysfunction and corresponding behaviors in Shank mouse mutants may help dissect the pathophysiology of ASD, but also highlight divergent phenotypes that arise from different mutations in the same gene. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Regulation of dendritic spine morphology and synaptic function by Shank and Homer.

            Carlo Sala, Valentin Piëch, Nathan Wilson … (2001)
            The Shank family of proteins interacts with NMDA receptor and metabotropic glutamate receptor complexes in the postsynaptic density (PSD). Targeted to the PSD by a PDZ-dependent mechanism, Shank promotes the maturation of dendritic spines and the enlargement of spine heads via its ability to recruit Homer to postsynaptic sites. Shank and Homer cooperate to induce accumulation of IP3 receptors in dendritic spines and formation of putative multisynapse spines. In addition, postsynaptic expression of Shank enhances presynaptic function, as measured by increased minifrequency and FM4-64 uptake. These data suggest a central role for the Shank scaffold in the structural and functional organization of the dendritic spine and synaptic junction.
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              Studying noncovalent protein complexes by electrospray ionization mass spectrometry.

              J A Loo (2015)
              Electrospray ionization mass spectrometry has been used to study protein interactions driven by noncovalent forces. The gentleness of the electrospray ionization process allows intact protein complexes to be directly detected by mass spectrometry. Evidence from the growing body of literature suggests that the ESI-MS observations for these weakly bound systems reflect, to some extent, the nature of the interaction found in the condensed phase. Stoichiometry of the complex can be easily obtained from the resulting mass spectrum because the molecular weight of the complex is directly measured. For the study of protein interactions, ESI-MS is complementary to other biophysical methods, such as NMR and analytical ultracentrifugation. However, mass spectrometry offers advantages in speed and sensitivity. The experimental variables that play a role in the outcome of ESI-MS studies of noncovalently bound complexes are reviewed. Several applications of ESI-MS are discussed, including protein interactions with metal ions and nucleic acids and subunit protein structures (quaternary structure).
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                Author and article information

                Contributors
                Heidar-Ali Tajmir-Riahi: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 26 February 2016
                Publication date Collection: 2016
                Volume: 11
                Issue: 2
                Electronic Location Identifier: e0149580
                Affiliations
                [1 ]Department of Chemistry, Centre of Novel Biomaterials, The Chinese University of Hong Kong, Shatin, Hong Kong, China
                [2 ]Department of Applied Biology & Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
                University of Quebec at Trois-Rivieres, CANADA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JL JX. Performed the experiments: JL ML BZ. Analyzed the data: JL ML BZ. Contributed reagents/materials/analysis tools: JX ZY. Wrote the paper: JL JX.

                Article
                Publisher ID: PONE-D-15-38470
                DOI: 10.1371/journal.pone.0149580
                PMC ID: 4769301
                PubMed ID: 26918521
                SO-VID: b7eae597-5f8a-457e-9a9e-73cd49348e3c
                Copyright © © 2016 Liu et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 31 August 2015
                Date accepted : 1 February 2016
                Page count
                Figures: 8, Tables: 0, Pages: 12
                Funding
                This work was supported by the Research Grants Council, Early Career Scheme grant CUHK 404812 (website: http://www.ugc.edu.hk/eng/rgc/fund/grants.htm#a), the Research Grants Council, General Research Fund grants 403711 and 404413 (website: http://www.ugc.edu.hk/eng/rgc/fund/grants.htm#b), and the Research Grants Council, Areas of Excellence Scheme, AoE/M-09/12 (website: http://www.ugc.edu.hk/eng/ugc/activity/aoes/aoes.htm). Prof. Xia received all the funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Research and Analysis Methods
                Subject: Chemical Synthesis
                Subject: Biosynthetic Techniques
                Subject: Peptide Synthesis
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Peptides
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Stoichiometry
                Subject: Research and Analysis Methods
                Subject: Chemical Characterization
                Subject: Binding Analysis
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Analytical Chemistry
                Subject: Mass Spectrometry
                Subject: Mass Spectra
                Subject: Research and Analysis Methods
                Subject: Spectrum Analysis Techniques
                Subject: Mass Spectrometry
                Subject: Mass Spectra
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Proteins
                Subject: Protein Interactions
                Subject: Research and Analysis Methods
                Subject: Chemical Characterization
                Subject: Calorimetry
                Subject: Isothermal Titration Calorimetry
                Subject: Research and Analysis Methods
                Subject: Chromatographic Techniques
                Subject: Liquid Chromatography
                Subject: High Performance Liquid Chromatography
                Custom metadata
                Data Availability All relevant data are within the paper and its Supporting Information files.

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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