A structural classification of the variant surface glycoproteins of the African trypanosome.
| Title: | A structural classification of the variant surface glycoproteins of the African trypanosome. |
|---|---|
| Authors: | Đaković S; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany.; Zeelen JP; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany.; Gkeka A; Division of Immune Diversity, German Cancer Research Center, Heidelberg, Germany.; Chandra M; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany.; Division of Immune Diversity, German Cancer Research Center, Heidelberg, Germany.; van Straaten M; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany.; Foti K; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany.; Zhong J; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany.; Vlachou EP; Division of Immune Diversity, German Cancer Research Center, Heidelberg, Germany.; Aresta-Branco F; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany.; Division of Immune Diversity, German Cancer Research Center, Heidelberg, Germany.; Verdi JP; Division of Immune Diversity, German Cancer Research Center, Heidelberg, Germany.; Papavasiliou FN; Division of Immune Diversity, German Cancer Research Center, Heidelberg, Germany.; Stebbins CE; Division of Structural Biology of Infection and Immunity, German Cancer Research Center, Heidelberg, Germany. |
| Source: | PLoS neglected tropical diseases [PLoS Negl Trop Dis] 2023 Sep 01; Vol. 17 (9), pp. e0011621. Date of Electronic Publication: 2023 Sep 01 (Print Publication: 2023). |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Public Library of Science Country of Publication: United States NLM ID: 101291488 Publication Model: eCollection Cited Medium: Internet ISSN: 1935-2735 (Electronic) Linking ISSN: 19352727 NLM ISO Abbreviation: PLoS Negl Trop Dis Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: San Francisco, CA : Public Library of Science |
| MeSH Terms: | Antigenic Variation* ; Membrane Glycoproteins* ; Trypanosoma* ; Protozoan Proteins*; Membrane Proteins |
| Abstract: | Long-term immune evasion by the African trypanosome is achieved through repetitive cycles of surface protein replacement with antigenically distinct versions of the dense Variant Surface Glycoprotein (VSG) coat. Thousands of VSG genes and pseudo-genes exist in the parasite genome that, together with genetic recombination mechanisms, allow for essentially unlimited immune escape from the adaptive immune system of the host. The diversity space of the "VSGnome" at the protein level was thought to be limited to a few related folds whose structures were determined more than 30 years ago. However, recent progress has shown that the VSGs possess significantly more architectural variation than had been appreciated. Here we combine experimental X-ray crystallography (presenting structures of N-terminal domains of coat proteins VSG11, VSG21, VSG545, VSG558, and VSG615) with deep-learning prediction using Alphafold to produce models of hundreds of VSG proteins. We classify the VSGnome into groups based on protein architecture and oligomerization state, contextualize recent bioinformatics clustering schemes, and extensively map VSG-diversity space. We demonstrate that in addition to the structural variability and post-translational modifications observed thus far, VSGs are also characterized by variations in oligomerization state and possess inherent flexibility and alternative conformations, lending additional variability to what is exposed to the immune system. Finally, these additional experimental structures and the hundreds of Alphafold predictions confirm that the molecular surfaces of the VSGs remain distinct from variant to variant, supporting the hypothesis that protein surface diversity is central to the process of antigenic variation used by this organism during infection.; (Copyright: © 2023 Đaković et al. 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.) |
| Competing Interests: | The authors declare that no competing interests exist. |
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| Substance Nomenclature: | 0 (Membrane Glycoproteins); 0 (Membrane Proteins); 0 (Protozoan Proteins) |
| Entry Date(s): | Date Created: 20230901 Date Completed: 20230918 Latest Revision: 20230930 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC10501684 |
| DOI: | 10.1371/journal.pntd.0011621 |
| PMID: | 37656766 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't