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      The Role of Oligomerization and Cooperative Regulation in Protein Function: The Case of Tryptophan Synthase

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      PLoS Computational Biology
      Public Library of Science

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          Abstract

          The oligomerization/co-localization of protein complexes and their cooperative regulation in protein function is a key feature in many biological systems. The synergistic regulation in different subunits often enhances the functional properties of the multi-enzyme complex. The present study used molecular dynamics and Brownian dynamics simulations to study the effects of allostery, oligomerization and intermediate channeling on enhancing the protein function of tryptophan synthase (TRPS). TRPS uses a set of α/β–dimeric units to catalyze the last two steps of L-tryptophan biosynthesis, and the rate is remarkably slower in the isolated monomers. Our work shows that without their binding partner, the isolated monomers are stable and more rigid. The substrates can form fairly stable interactions with the protein in both forms when the protein reaches the final ligand–bound conformations. Our simulations also revealed that the α/β–dimeric unit stabilizes the substrate–protein conformation in the ligand binding process, which lowers the conformation transition barrier and helps the protein conformations shift from an open/inactive form to a closed/active form. Brownian dynamics simulations with a coarse-grained model illustrate how protein conformations affect substrate channeling. The results highlight the complex roles of protein oligomerization and the fine balance between rigidity and dynamics in protein function.

          Author Summary

          Conformational changes of enzymes are often related to regulating and creating an optimal environment for efficient chemistry. An increasing number of evidences also indicate that oligomerization/co-localization of proteins contributes to the efficiency of metabolic pathways. Although static structures have been available for many multi-enzyme complexes, their efficiency is also governed by the synergistic regulation between the multi-units. Our study applies molecular dynamics and Brownian dynamics simulations to the model system, the tryptophan synthase complex. The multi-enzyme complex is a bienzyme nanomachine and its catalytic activity is intimately related to the allosteric signaling and the metabolite transfer between its α– and β–subunits connected by a 25-Å long channel. Our studies suggest that the binding partner is crucial for the ligand binding processes. Although the isolated monomers are stable in the ligand–free state and can form stable interaction if the substrate is in the final bound conformation, it has higher energy barrier when ligand binds to the active site. We also show that the channel does not always exist, but it may be blocked before the enzyme reaches its final bound conformation. The results highlight the importance of forming protein complexes and the cooperative changes during different states.

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          Cell signaling in space and time: where proteins come together and when they're apart.

          Signal transduction can be defined as the coordinated relay of messages derived from extracellular cues to intracellular effectors. More simply put, information received on the cell surface is processed across the plasma membrane and transmitted to intracellular targets. This requires that the activators, effectors, enzymes, and substrates that respond to cellular signals come together when they need to.
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            The power of two: protein dimerization in biology.

            The self-association of proteins to form dimers and higher-order oligomers is a very common phenomenon. Recent structural and biophysical studies show that protein dimerization or oligomerization is a key factor in the regulation of proteins such as enzymes, ion channels, receptors and transcription factors. In addition, self-association can help to minimize genome size, while maintaining the advantages of modular complex formation. Oligomerization, however, can also have deleterious consequences when nonnative oligomers associated with pathogenic states are generated. Specific protein dimerization is integral to biological function, structure and control, and must be under substantial selection pressure to be maintained with such frequency throughout biology.
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              Linkage between dynamics and catalysis in a thermophilic-mesophilic enzyme pair.

              A fundamental question is how enzymes can accelerate chemical reactions. Catalysis is not only defined by actual chemical steps, but also by enzyme structure and dynamics. To investigate the role of protein dynamics in enzymatic turnover, we measured residue-specific protein dynamics in hyperthermophilic and mesophilic homologs of adenylate kinase during catalysis. A dynamic process, the opening of the nucleotide-binding lids, was found to be rate-limiting for both enzymes as measured by NMR relaxation. Moreover, we found that the reduced catalytic activity of the hyperthermophilic enzyme at ambient temperatures is caused solely by a slower lid-opening rate. This comparative and quantitative study of activity, structure and dynamics revealed a close link between protein dynamics and catalytic turnover.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Comput Biol
                plos
                ploscomp
                PLoS Computational Biology
                Public Library of Science (San Francisco, USA )
                1553-734X
                1553-7358
                November 2010
                November 2010
                11 November 2010
                : 6
                : 11
                : e1000994
                Affiliations
                [1]Department of Chemistry, University of California, Riverside, Riverside, California, United States of America
                University of Parma, Italy
                Author notes

                Conceived and designed the experiments: MQF CeAC. Performed the experiments: MQF CeAC. Analyzed the data: MQF CeAC. Contributed reagents/materials/analysis tools: CeAC. Wrote the paper: MQF CeAC.

                Article
                10-PLCB-RA-2275R3
                10.1371/journal.pcbi.1000994
                2978696
                21085641
                c0a424a7-0e8f-48bf-94c2-35d3bdcac535
                Fatmi, Chang. 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
                : 20 May 2010
                : 8 October 2010
                Page count
                Pages: 14
                Categories
                Research Article
                Biochemistry/Macromolecular Chemistry
                Biochemistry/Protein Chemistry
                Biochemistry/Theory and Simulation
                Biophysics
                Biophysics/Biomacromolecule-Ligand Interactions
                Biophysics/Theory and Simulation

                Quantitative & Systems biology
                Quantitative & Systems biology

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