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The Two Sides of Complement C3d: Evolution of Electrostatics in a Link between Innate and Adaptive Immunity

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PLoS Computational Biology

Public Library of Science

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      Abstract

      The interaction between complement fragment C3d and complement receptor 2 (CR2) is a key aspect of complement immune system activation, and is a component in a link between innate and adaptive immunities. The complement immune system is an ancient mechanism for defense, and can be found in species that have been on Earth for the last 600 million years. However, the link between the complement system and adaptive immunity, which is formed through the association of the B-cell co-receptor complex, including the C3d-CR2 interaction, is a much more recent adaptation. Human C3d and CR2 have net charges of −1 and +7 respectively, and are believed to have evolved favoring the role of electrostatics in their functions. To investigate the role of electrostatics in the function and evolution of human C3d and CR2, we have applied electrostatic similarity methods to identify regions of evolutionarily conserved electrostatic potential based on 24 homologues of complement C3d and 4 homologues of CR2. We also examine the effects of structural perturbation, as introduced through molecular dynamics and mutations, on spatial distributions of electrostatic potential to identify perturbation resistant regions, generated by so-called electrostatic “hot-spots”. Distributions of electrostatic similarity based on families of perturbed structures illustrate the presence of electrostatic “hot-spots” at the two functional sites of C3d, while the surface of CR2 lacks electrostatic “hot-spots” despite its excessively positive nature. We propose that the electrostatic “hot-spots” of C3d have evolved to optimize its dual-functionality (covalently attaching to pathogen surfaces and interaction with CR2), which are both necessary for the formation B-cell co-receptor complexes. Comparison of the perturbation resistance of the electrostatic character of the homologues of C3d suggests that there was an emergence of a new role of electrostatics, and a transition in the function of C3d, after the divergence of jawless fish.

      Author Summary

      Complement fragment C3d is a thioester-containing protein that is a key component/domain in the complement system, an ancient line of defense, due to its ability to covalently attach to pathogen cell surfaces, such as bacteria. As the immune system evolved in complexity, from acellular defense mechanisms to multicellular systems with memory, so has the function of C3d. In humans, but not lower species such as invertebrates, C3d attached to pathogen surfaces binds B-cell co-receptor CR2, in conjunction with an antibody/antigen complex, forming a link between the innate and adaptive immune systems. The C3d-CR2 interaction ultimately increases B-cell sensitivity to the C3d tagged pathogen by 1,000–10,000 fold, and is known to be driven by electrostatic forces. Since electrostatics are crucial to the C3d-CR2 interaction, it is likely that probing the evolution of the electrostatics of C3d and CR2 will provide insight into this gained function. To this end, we employ a novel computational approach for identifying the electrostatic “hot-spots” of C3d and CR2, which are produced by clusters of like-charged residues found on the surface of the protein. Electrostatic “hot-spots” are often evolutionarily favored and in this study provide new insight into the evolution of C3d in its role in a link between innate and adaptive immunity.

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      Most cited references 27

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        The design, implementation, and capabilities of an extensible visualization system, UCSF Chimera, are discussed. Chimera is segmented into a core that provides basic services and visualization, and extensions that provide most higher level functionality. This architecture ensures that the extension mechanism satisfies the demands of outside developers who wish to incorporate new features. Two unusual extensions are presented: Multiscale, which adds the ability to visualize large-scale molecular assemblies such as viral coats, and Collaboratory, which allows researchers to share a Chimera session interactively despite being at separate locales. Other extensions include Multalign Viewer, for showing multiple sequence alignments and associated structures; ViewDock, for screening docked ligand orientations; Movie, for replaying molecular dynamics trajectories; and Volume Viewer, for display and analysis of volumetric data. A discussion of the usage of Chimera in real-world situations is given, along with anticipated future directions. Chimera includes full user documentation, is free to academic and nonprofit users, and is available for Microsoft Windows, Linux, Apple Mac OS X, SGI IRIX, and HP Tru64 Unix from http://www.cgl.ucsf.edu/chimera/. Copyright 2004 Wiley Periodicals, Inc.
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          Evaluation of the electrostatic properties of biomolecules has become a standard practice in molecular biophysics. Foremost among the models used to elucidate the electrostatic potential is the Poisson-Boltzmann equation; however, existing methods for solving this equation have limited the scope of accurate electrostatic calculations to relatively small biomolecular systems. Here we present the application of numerical methods to enable the trivially parallel solution of the Poisson-Boltzmann equation for supramolecular structures that are orders of magnitude larger in size. As a demonstration of this methodology, electrostatic potentials have been calculated for large microtubule and ribosome structures. The results point to the likely role of electrostatics in a variety of activities of these structures.
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            Author and article information

            Affiliations
            Department of Bioengineering, University of California, Riverside, Riverside, California, United States of America
            University of California San Diego, United States of America
            Author notes

            The authors have declared that no competing interests exist.

            Conceived and designed the experiments: CAK DM. Performed the experiments: CAK. Analyzed the data: CAK DM. Wrote the paper: CAK DM.

            Contributors
            Role: Editor
            Journal
            PLoS Comput Biol
            PLoS Comput. Biol
            plos
            ploscomp
            PLoS Computational Biology
            Public Library of Science (San Francisco, USA )
            1553-734X
            1553-7358
            December 2012
            December 2012
            27 December 2012
            : 8
            : 12
            23300422 3531323 PCOMPBIOL-D-12-00801 10.1371/journal.pcbi.1002840

            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.

            Counts
            Pages: 8
            Funding
            This work was supported by the UCR Chancellor’s Strategic Initiatives grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
            Categories
            Research Article
            Biology
            Computational Biology
            Biophysic Al Simulations
            Immunology
            Immune System
            Complement System

            Quantitative & Systems biology

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