Membrane fusion protein

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Membrane fusion proteins (not to be confused with chimeric or fusion proteins) are proteins that cause fusion of biological membranes. Membrane fusion is critical for many biological processes, especially in eukaryotic development and viral entry. Fusion proteins can originate from genes encoded by infectious enveloped viruses, ancient retroviruses integrated into the host genome, [1] or solely by the host genome. [2] Post-transcriptional modifications made to the fusion proteins by the host, namely addition and modification of glycans and acetyl groups, can drastically affect fusogenicity (the ability to fuse). [3]

Contents

Fusion in eukaryotes

Eukaryotic genomes contain several gene families, of host and viral origin, which encode products involved in driving membrane fusion. While adult somatic cells do not typically undergo membrane fusion under normal conditions, gametes and embryonic cells follow developmental pathways to non-spontaneously drive membrane fusion, such as in placental formation, syncytiotrophoblast formation, and neurodevelopment. Fusion pathways are also involved in the development of musculoskeletal and nervous system tissues. Vesicle fusion events involved in neurotransmitter trafficking also relies on the catalytic activity of fusion proteins.

SNARE family

The SNARE exocytosis machinery Exocytosis-machinery.jpg
The SNARE exocytosis machinery

The SNARE family includes bona fide eukaryotic fusion proteins. They are only found in eukaryotes and their closest archaeal relatives like Heimdallarchaeota. [4]

Retroviral

These proteins originate from the env gene of endogenous retroviruses. They are domesticated viral class I fusion proteins.

HAP2 family

HAP2 is a fusexin (similar to viral class II) found in diverse eukaryotes including Toxoplasma , vascular plants, and fruit flies. This protein is essential for gamete fusion in these organisms. [6] Its origin is unclear, as the broader grouping of fusexins could be older than the viral class II with the discovery of archaeal homologs. [7]

Pathogenic viral fusion

Enveloped viruses readily overcome the thermodynamic barrier of merging two plasma membranes by storing kinetic energy in fusion (F) proteins. F proteins can be independently expressed on host cell surfaces which can either (1) drive the infected cell to fuse with neighboring cells, forming a syncytium, or (2) be incorporated into a budding virion from the infected cell which leads to the full emancipation of plasma membrane from the host cell. Some F components solely drive fusion while a subset of F proteins can interact with host factors. There are four groups of fusion proteins categorized by their structure and mechanism of fusion. [8]

Despite their very different structure and presumably different origins, classes I, II, and III all work by forming a trimer of hairpins. [9]

Class I

Class I fusion proteins resemble influenzavirus hemagglutinin in their structure. Post-fusion, the active site has a trimer of α-helical coiled-coils. The binding domain is rich in α-helices and hydrophobic fusion peptides located near the N-terminus (some examples show internal fusion peptides, however). [9] Fusion conformation change can often be controlled by pH. [10]

Class II

Class II proteins are dominant in β-sheets and the catalytic sites are localized in the core region. The peptide regions required to drive fusion are formed from the turns between the β-sheets. [9] They usually start as dimers, becoming a trimer as fusion happens. [11] [10]

Class III

Class III fusion proteins are distinct from I and II. They typically consist of five structural domains, where domains 1, 2 and 4 often contain more β-sheets and domains 3 and 5 are richer in α-helices (defining domain 1 as being closer to the N-terminus and 5 closer to the C-terminus). In the pre-fusion state, the domains nest, with domain 1 protected by domain 2, which is nested in domain 3, which is protected by domain 4. Domain 1 contains a bipartite site, likely for membrane fusion, within the loops connecting its long beta strands, and domain 5 serves as a linker between domain 4 and the C-terminal membrane-proximal and transmembrane domains. Domain 3 refolds upon fusion, while domain 5 loses its alpha helical structure. [9] [10]

Others

A number of fusion proteins belong to none of the three main classes. [9]

Poxviruses employ a multiprotein system of 11 different genes and their relatives in the broader group of Nucleocytoviricota appear to do likewise. [12] The structure of the fusion complex is not yet resolved. Scientists have produced some information on what each of the components bind to, but still not enough to produce a full picture. [13] [14]

Hepadnaviridae, which includes the Hep B virus, uses different forms of the surface antigen (HBsAg - S, M and L) to fuse. [9] It was found in 2021 that it has a fusion peptide in preS1, which is found in the L form. [15]

FAST

Fusion-associated small transmembrane proteins (FAST) are the smallest type of fusion protein. They are found in reoviruses, which are non-enveloped viruses and are specialized for cell-cell rather than virus-cell fusion, forming syncytia. They are the only known membrane fusion proteins found in non-enveloped viruses. [16] They exploit the cell-cell adhesion machinery to achieve initial attachment. They might encourage fusion by inducing membrane curvature using a variety of hydrophobic motifs and modified residues. [17]

Examples

Fusion proteinAbbreviationClassVirus familyExample virusesExample PDB/AlphaFoldReference
Coronavirus spike protein SI Coronaviridae SARS-CoV, SARS-CoV-2 PDB: 6VSB ​ [18] [19]
Ebolavirus glycoprotein GPI Filoviridae Zaire-, Sudan- ebolaviruses, Marburgvirus PDB: 3CSY ​ [8] [20]
Glycoprotein 41 Gp41I Retroviridae HIV PDB: 4CC8 ​ [8] [20]
Hemagglutinin H, HA, HNI Orthomyxoviridae, Paramyxoviridae Influenza virus, measles virus, mumps virus PDB: 4QY1 ​ [8] [20]
Alphavirus envelope protein E1 E1II Togaviridae Semliki Forest virus PDB: 6NK5 ​ [8] [20]
Flavivirus envelope protein EII Flaviviridae Dengue virus, West Nile virus PDB: 1K4R ​ [8] [20]
Herpesvirus glycoprotein B gBIII Herpesviridae HSV-1 PDB: 5V2S ​ [8] [21]
VSV G GIII Rhabdoviridae Vesicular stomatitis virus, rabies lyssavirus PDB: 6LGX ​ [8] [21]
Fusion-associated small transmembrane protein FASTFAST Reoviridae Avian orthoreovirus PDB: 2MNS ​, Q9UM95 [8] [17]

Cross-group families

Fusexin

The fusexin family consists of eukaryotic HAP2/GCS1, eukaryotic EFF-1, viral "class II", and haloarchaeal Fsx1. They all share a common fold and fuse membranes. [7] In an unrooted phylogenetic tree from 2021, HAP2/GCS1 and EFF-1/AFF-1 occupy two ends of the tree, the middle being occupied by viral sequences; this suggests that they may have been acquired separately. [11] The latest structure-based unrooted phylogenetic tree of Brukman et al. (2022), which takes into account the newly-discovered archaeal sequences, shows that Fsx1 groups with HAP2/GCS1, and that they are separated from EFF-1 by a number of viral sequences. Based on where the root is placed, a number of different hypotheses regarding the history of these families – their horizontal transfer and vertical inheritance – can be generated. [7] Older comparisons excluding archaeal sequences would strongly favor an interpretation where HAP2/GCS1 is acquired from a virus, [6] but the grouping of Fsx1 with HAP2/GCS1 has allowed the possibility of a much more ancient source. [7]

See also

References

  1. ↑ Classification of viral fusion proteins in TCDB database
  2. ↑ Klapper R, Stute C, Schomaker O, Strasser T, Janning W, Renkawitz-Pohl R, Holz A (January 2002). "The formation of syncytia within the visceral musculature of the Drosophila midgut is dependent on duf, sns and mbc". Mechanisms of Development. 110 (1–2): 85–96. doi: 10.1016/S0925-4773(01)00567-6 . PMID   11744371.
  3. ↑ Ortega V, Stone JA, Contreras EM, Iorio RM, Aguilar HC (January 2019). "Addicted to sugar: roles of glycans in the order Mononegavirales". Glycobiology. 29 (1): 2–21. doi:10.1093/glycob/cwy053. PMC   6291800 . PMID   29878112.
  4. ↑ Neveu E, Khalifeh D, Salamin N, Fasshauer D (July 2020). "Prototypic SNARE Proteins Are Encoded in the Genomes of Heimdallarchaeota, Potentially Bridging the Gap between the Prokaryotes and Eukaryotes" (PDF). Current Biology. 30 (13): 2468–2480.e5. Bibcode:2020CBio...30E2468N. doi: 10.1016/j.cub.2020.04.060 . PMID   32442459. S2CID   218762979.
  5. ↑ Mangeney M, Renard M, Schlecht-Louf G, Bouallaga I, Heidmann O, Letzelter C, et al. (December 2007). "Placental syncytins: Genetic disjunction between the fusogenic and immunosuppressive activity of retroviral envelope proteins". Proceedings of the National Academy of Sciences of the United States of America. 104 (51): 20534–9. Bibcode:2007PNAS..10420534M. doi: 10.1073/pnas.0707873105 . PMC   2154466 . PMID   18077339.
  6. 1 2 Fédry J, Liu Y, Péhau-Arnaudet G, Pei J, Li W, Tortorici MA, et al. (February 2017). "The Ancient Gamete Fusogen HAP2 Is a Eukaryotic Class II Fusion Protein". Cell. 168 (5): 904–915.e10. doi:10.1016/j.cell.2017.01.024. PMC   5332557 . PMID   28235200.
  7. 1 2 3 4 Moi, David; Nishio, Shunsuke; Li, Xiaohui; Valansi, Clari; Langleib, Mauricio; Brukman, Nicolas G.; Flyak, Kateryna; Dessimoz, Christophe; de Sanctis, Daniele; Tunyasuvunakool, Kathryn; Jumper, John; Graña, Martin; Romero, Héctor; Aguilar, Pablo S.; Jovine, Luca; Podbilewicz, Benjamin (6 July 2022). "Discovery of archaeal fusexins homologous to eukaryotic HAP2/GCS1 gamete fusion proteins". Nature Communications. 13 (1): 3880. Bibcode:2022NatCo..13.3880M. doi:10.1038/s41467-022-31564-1. PMC   9259645 . PMID   35794124.
  8. 1 2 3 4 5 6 7 8 9 Podbilewicz, Benjamin (11 October 2014). "Virus and Cell Fusion Mechanisms". Annual Review of Cell and Developmental Biology. 30 (1): 111–139. doi:10.1146/annurev-cellbio-101512-122422. PMID   25000995.
  9. 1 2 3 4 5 6 White JM, Delos SE, Brecher M, Schornberg K (2008). "Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme". Critical Reviews in Biochemistry and Molecular Biology. 43 (3): 189–219. doi:10.1080/10409230802058320. PMC   2649671 . PMID   18568847.
  10. 1 2 3 Backovic M, Jardetzky TS (April 2009). "Class III viral membrane fusion proteins". Current Opinion in Structural Biology. 19 (2): 189–96. doi:10.1016/j.sbi.2009.02.012. PMC   3076093 . PMID   19356922.
  11. 1 2 Brukman, Nicolas G.; Li, Xiaohui; Podbilewicz, Benjamin (10 January 2022). "Fusexins, HAP2/GCS1 and Evolution of Gamete Fusion". Frontiers in Cell and Developmental Biology. 9. doi: 10.3389/fcell.2021.824024 . PMC   8784728 . PMID   35083224.
  12. ↑ Kao, Sheng; Kao, Chi-Fei; Chang, Wen; Ku, Chuan (13 April 2023). "Widespread Distribution and Evolution of Poxviral Entry-Fusion Complex Proteins in Giant Viruses". Microbiology Spectrum. 11 (2): e0494422. doi:10.1128/spectrum.04944-22. PMC   10100723 . PMID   36912656.
  13. ↑ Moss, B (December 2016). "Membrane fusion during poxvirus entry". Seminars in Cell & Developmental Biology. 60: 89–96. doi:10.1016/j.semcdb.2016.07.015. PMC   5161597 . PMID   27423915.
  14. ↑ Schin, AM; Diesterbeck, US; Moss, B (26 July 2021). "Insights into the Organization of the Poxvirus Multicomponent Entry-Fusion Complex from Proximity Analyses in Living Infected Cells". Journal of Virology. 95 (16): e0085221. doi:10.1128/JVI.00852-21. PMC   8312868 . PMID   34076488.
  15. ↑ Pérez-Vargas, Jimena; Teppa, Elin; Amirache, Fouzia; Boson, Bertrand; Pereira de Oliveira, Rémi; Combet, Christophe; Böckmann, Anja; Fusil, Floriane; Freitas, Natalia; Carbone, Alessandra; Cosset, François-Loïc (30 June 2021). "A fusion peptide in preS1 and the human protein disulfide isomerase ERp57 are involved in hepatitis B virus membrane fusion process". eLife. 10. doi: 10.7554/eLife.64507 . PMC   8282342 . PMID   34190687.
  16. ↑ Shmulevitz, Maya; Duncan, Roy (1 March 2000). "A new class of fusion-associated small transmembrane (FAST) proteins encoded by the non-enveloped fusogenic reoviruses". The EMBO Journal. 19 (5): 902–912. doi:10.1093/emboj/19.5.902. PMC   305630 . PMID   10698932.
  17. 1 2 Ciechonska, Marta; Duncan, Roy (December 2014). "Reovirus FAST proteins: virus-encoded cellular fusogens". Trends in Microbiology. 22 (12): 715–724. doi:10.1016/j.tim.2014.08.005. PMID   25245455.
  18. ↑ Li, Fang (29 September 2016). "Structure, Function, and Evolution of Coronavirus Spike Proteins". Annual Review of Virology. 3 (1): 237–261. doi:10.1146/annurev-virology-110615-042301. PMC   5457962 . PMID   27578435.
  19. ↑ Zhu, Chaogeng; He, Guiyun; Yin, Qinqin; Zeng, Lin; Ye, Xiangli; Shi, Yongzhong; Xu, Wei (October 2021). "Molecular biology of the SARs-CoV-2 spike protein: A review of current knowledge". Journal of Medical Virology. 93 (10): 5729–5741. doi: 10.1002/jmv.27132 . PMC   8427004 . PMID   34125455.
  20. 1 2 3 4 5 White, Judith M.; Whittaker, Gary R. (June 2016). "Fusion of Enveloped Viruses in Endosomes". Traffic. 17 (6): 593–614. doi:10.1111/tra.12389. PMC   4866878 . PMID   26935856.
  21. 1 2 Baquero, Eduard; Albertini, Aurélie AV; Gaudin, Yves (August 2015). "Recent mechanistic and structural insights on class III viral fusion glycoproteins". Current Opinion in Structural Biology. 33: 52–60. doi:10.1016/j.sbi.2015.07.011. PMID   26277251.
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