Membrane fusion protein

Last updated

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 include 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.x [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 5 structural domains, where domain 1 and 2 localized to the C-terminal end often contain more β-sheets and domains 2-5 closer to the N-terminal side are richer in α-helices. In the pre-fusion state, the later domains nest and protect domain 1 (i.e. domain 1 is protected by domain 2, which is nested in domain 3, which is protected by domain 4). Domain 1 contains the catalytic site for membrane fusion. [10] [9]

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 M and L forms. [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

Related Research Articles

A syncytium or symplasm is a multinucleate cell that can result from multiple cell fusions of uninuclear cells, in contrast to a coenocyte, which can result from multiple nuclear divisions without accompanying cytokinesis. The muscle cell that makes up animal skeletal muscle is a classic example of a syncytium cell. The term may also refer to cells interconnected by specialized membranes with gap junctions, as seen in the heart muscle cells and certain smooth muscle cells, which are synchronized electrically in an action potential.

<span class="mw-page-title-main">Viral protein</span>

The term viral protein refers to both the products of the genome of a virus and any host proteins incorporated into the viral particle. Viral proteins are grouped according to their functions, and groups of viral proteins include structural proteins, nonstructural proteins, regulatory proteins, and accessory proteins. Viruses are non-living and do not have the means to reproduce on their own, instead depending on their host cell's machinery to do this. Thus, viruses do not code for most of the proteins required for their replication and the translation of their mRNA into viral proteins, but use proteins encoded by the host cell for this purpose.

<span class="mw-page-title-main">Viral replication</span> Formation of biological viruses during the infection process

Viral replication is the formation of biological viruses during the infection process in the target host cells. Viruses must first get into the cell before viral replication can occur. Through the generation of abundant copies of its genome and packaging these copies, the virus continues infecting new hosts. Replication between viruses is greatly varied and depends on the type of genes involved in them. Most DNA viruses assemble in the nucleus while most RNA viruses develop solely in cytoplasm.

<i>Alphavirus</i> Genus of viruses

Alphavirus is a genus of RNA viruses, the sole genus in the Togaviridae family. Alphaviruses belong to group IV of the Baltimore classification of viruses, with a positive-sense, single-stranded RNA genome. There are 32 alphavirus species, which infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses, as well as invertebrates. Alphaviruses that can infect both vertebrates and arthropods are referred dual-host alphaviruses, while insect-specific alphaviruses such as Eilat virus and Yada yada virus are restricted to their competent arthropod vector. Transmission between species and their vertebrate hosts occurs mainly via mosquitoes, making the alphaviruses a member of the collection of arboviruses – or arthropod-borne viruses. Alphavirus particles are enveloped, have a 70 nm diameter, tend to be spherical, and have a 40 nm isometric nucleocapsid.

Viral eukaryogenesis is the hypothesis that the cell nucleus of eukaryotic life forms evolved from a large DNA virus in a form of endosymbiosis within a methanogenic archaeon or a bacterium. The virus later evolved into the eukaryotic nucleus by acquiring genes from the host genome and eventually usurping its role. The hypothesis was first proposed by Philip Bell in 2001 and was further popularized with the discovery of large, complex DNA viruses that are capable of protein biosynthesis.

<i>Pseudomonas virus phi6</i> Species of virus

Φ6 is the best-studied bacteriophage of the virus family Cystoviridae. It infects Pseudomonas bacteria. It has a three-part, segmented, double-stranded RNA genome, totalling ~13.5 kb in length. Φ6 and its relatives have a lipid membrane around their nucleocapsid, a rare trait among bacteriophages. It is a lytic phage, though under certain circumstances has been observed to display a delay in lysis which may be described as a "carrier state".

<span class="mw-page-title-main">Viral envelope</span> Outermost layer of many types of the infectious agent

A viral envelope is the outermost layer of many types of viruses. It protects the genetic material in their life cycle when traveling between host cells. Not all viruses have envelopes. A viral envelope protein or E protein is a protein in the envelope, which may be acquired by the capsid from an infected host cell.

<span class="mw-page-title-main">Viral entry</span> Earliest stage of infection in the viral life cycle

Viral entry is the earliest stage of infection in the viral life cycle, as the virus comes into contact with the host cell and introduces viral material into the cell. The major steps involved in viral entry are shown below. Despite the variation among viruses, there are several shared generalities concerning viral entry.

<span class="mw-page-title-main">Spike protein</span> Glycoprotein spike on a viral capsid or viral envelope

In virology, a spike protein or peplomer protein is a protein that forms a large structure known as a spike or peplomer projecting from the surface of an enveloped virus. The proteins are usually glycoproteins that form dimers or trimers.

Env is a viral gene that encodes the protein forming the viral envelope. The expression of the env gene enables retroviruses to target and attach to specific cell types, and to infiltrate the target cell membrane.

A fusion mechanism is any mechanism by which cell fusion or virus–cell fusion takes place, as well as the machinery that facilitates these processes. Cell fusion is the formation of a hybrid cell from two separate cells. There are three major actions taken in both virus–cell fusion and cell–cell fusion: the dehydration of polar head groups, the promotion of a hemifusion stalk, and the opening and expansion of pores between fusing cells. Virus–cell fusions occur during infections of several viruses that are health concerns relevant today. Some of these include HIV, Ebola, and influenza. For example, HIV infects by fusing with the membranes of immune system cells. In order for HIV to fuse with a cell, it must be able to bind to the receptors CD4, CCR5, and CXCR4. Cell fusion also occurs in a multitude of mammalian cells including gametes and myoblasts.

<i>Lipothrixviridae</i> Family of viruses

Lipothrixviridae is a family of viruses in the order Ligamenvirales. Thermophilic archaea in the phylum Thermoproteota serve as natural hosts. There are 11 species in this family, assigned to 4 genera.

HAP2, also known as GCS1, is a family of membrane fusion proteins found in the sperm cell of diverse eukaryotes including Toxoplasma, thale cress, and fruit flies. This protein is essential for gamete fusion, and therefore fertilization, in these organisms.

<span class="mw-page-title-main">Syncytin-1</span> Protein found in humans

Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene. Syncytin-1 is a cell-cell fusion protein whose function is best characterized in placental development. The placenta in turn aids in embryo attachment to the uterus and establishment of a nutrient supply.

<span class="mw-page-title-main">Hemagglutinin</span> Substance that causes red blood cells to agglutinate

Hemagglutinins are homotrimeric glycoproteins present on the protein capsids of viruses in the Paramyxoviridae and Orthomyxoviridae families. Hemagglutinins are responsible for binding to receptors, sialic acid residues, on host cell membranes to initiate virus docking and infection.

<span class="mw-page-title-main">Lipid bilayer fusion</span>

In membrane biology, fusion is the process by which two initially distinct lipid bilayers merge their hydrophobic cores, resulting in one interconnected structure. If this fusion proceeds completely through both leaflets of both bilayers, an aqueous bridge is formed and the internal contents of the two structures can mix. Alternatively, if only one leaflet from each bilayer is involved in the fusion process, the bilayers are said to be hemifused. In hemifusion, the lipid constituents of the outer leaflet of the two bilayers can mix, but the inner leaflets remain distinct. The aqueous contents enclosed by each bilayer also remain separated.

Cell–cell fusogens are glycoproteins that facilitate the fusion of cell to cell membranes. Cell–cell fusion is critical for the merging of gamete genomes and the development of organs in multicellular organisms. Cell-cell fusion occurs when both actin cytoskeleton and fusogenic proteins properly rearrange across the cell membrane. This process is led by actin-propelled membrane protrusions.

Flock House virus (FHV) is in the Alphanodavirus genus of the Nodaviridae family of viruses. Flock House virus was isolated from a grass grub at the Flock House research station in Bulls, New Zealand. FHV is an extensively studied virus and is considered a model system for the study of other non-enveloped RNA viruses owing to its small size and genetic tractability, particularly to study the role of the transiently exposed hydrophobic gamma peptide and the metastability of the viral capsid. FHV can be engineered in insect cell culture allowing for the tailored production of native or mutant authentic virions or virus-like-particles. FHV is a platform for nanotechnology and nanomedicine, for example, for epitope display and vaccine development. Viral entry into host cells occurs via receptor-mediated endocytosis. Receptor binding initiates a sequence of events during which the virus exploits the host environment in order to deliver the viral cargo in to the host cytosol. Receptor binding prompts the meta-stability of the capsid–proteins, the coordinated rearrangements of which are crucial for subsequent steps in the infection pathway. In addition, the transient exposure of a covalently-independent hydrophobic γ-peptide is responsible for breaching cellular membranes and is thus essential for the viral entry of FHV into host cells.

Mammalian orthoreovirus (MRV) is a double-stranded RNA virus. It is a part of the family Reoviridae, as well as the subfamily Spinareovirinae. As seen in the name, the Mammalian Ortheoreovirus infects numerous mammalian species and vertebrates which serve as natural hosts. Some diseases that occur as a result of this virus or are associated with this virus include mild upper respiratory illness, and gastrointestinal illness. Examples of these are: upper respiratory tract syndromes, gastroenteritis, biliary atresia, obstructive hydrocephalus, jaundice, alopecia, conjunctivitis, and ‘oily hair’ associated with steatorrhea.

Rio Negro virus is an alphavirus that was first isolated in Argentina in 1980. The virus was first called Ag80-663 but was renamed to Rio Negro virus in 2005. It is a former member of the Venezuelan equine encephalitis complex (VEEC), which are a group of alphaviruses in the Americas that have the potential to emerge and cause disease. Río Negro virus was recently reclassified as a distinct species. Closely related viruses include Mucambo virus and Everglades virus.

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.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.