ArticlePLoS computational biology2012
The two sides of complement C3d: evolution of electrostatics in a link between innate and adaptive immunity.
Article in PLoS computational biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 27 citations in OpenAlex.
- Identification and Characterization of chCR2, a Protein That Binds Chicken Complement Component 3d.Journal of immunology (Baltimore, Md. : 1950) · 2023Article
- Dysregulation of the Enteric Nervous System in the Mid Colon of Complement Component 3 Knockout Mice with Constipation Phenotypes.International journal of molecular sciences · 2022Article
- Mutational signatures in GATA3 transcription factor and its DNA binding domain that stimulate breast cancer and HDR syndrome.Scientific reports · 2021Article
- Recent advances in user-friendly computational tools to engineer protein function.Briefings in bioinformatics · 2021Review
- Role of Electrostatic Hotspots in the Selectivity of Complement Control Proteins Toward Human and Bovine Complement Inhibition.Frontiers in molecular biosciences · 2021Article
- Better Epitope Discovery, Precision Immune Engineering, and Accelerated Vaccine Design Using Immunoinformatics Tools.Frontiers in immunology · 2020Review
- C1s Inhibition by BIVV009 (Sutimlimab) Prevents Complement-Enhanced Activation of Autoimmune Human B Cells In Vitro.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Emerging Roles of Complement in Psychiatric Disorders.Frontiers in psychiatry · 2019Review
- AESOP: A Python Library for Investigating Electrostatics in Protein Interactions.Biophysical journal · 2017Article
- Electrostatic Steering Accelerates C3d:CR2 Association.The journal of physical chemistry. B · 2016Article
- A Three-protein Charge Zipper Stabilizes a Complex Modulating Bacterial Gene Silencing.The Journal of biological chemistry · 2015Article
- Energetic evaluation of binding modes in the C3d and Factor H (CCP 19-20) complex.Protein science : a publication of the Protein Society · 2015Article
- Molecular analysis of the interaction between staphylococcal virulence factor Sbi-IV and complement C3d.Biophysical journal · 2014Article
- Electrostatic similarities between protein and small molecule ligands facilitate the design of protein-protein interaction inhibitors.PloS one · 2013Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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