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 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 domesticated viral class II fusion protein found in diverse eukaryotes including Toxoplasma , vascular plants, and fruit flies. This protein is essential for gamete fusion in these organisms. [5]

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. [6]

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. Fusion conformation change can often be controlled by pH. [7] [8]

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. [7] [8]

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. [7] [8]

Class IV

Class IV fusion proteins, better known as 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. [9] [10]

Examples

Fusion proteinAbbreviationClassVirus familyExample virusesReference
Coronavirus spike protein SI Coronaviridae SARS-CoV, SARS-CoV-2 [11] [12]
Ebolavirus glycoprotein GPI Filoviridae Zaire-, Sudan- ebolaviruses, Marburgvirus [6] [13]
Glycoprotein 41 Gp41I Retroviridae HIV [6] [13]
Hemagglutinin H, HA, HNI Orthomyxoviridae, Paramyxoviridae Influenza virus, measles virus, mumps virus [6] [13]
Alphavirus envelope protein E1 E1II Togaviridae Semliki Forest virus [6] [13]
Flavivirus envelope protein EII Flaviviridae Dengue virus, West Nile virus [6] [13]
Herpesvirus glycoprotein B gBIII Herpesviridae HSV-1 [6] [14]
VSV G GIII Rhabdoviridae Vesicular stomatitis virus, rabies lyssavirus [6] [14]
Fusion-associated small transmembrane protein FASTIV Reoviridae Avian orthoreovirus [6] [10]

See also

Related Research Articles

<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.

<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 alphaviruses, which infect various vertebrates such as humans, rodents, fish, birds, and larger mammals such as horses, as well as invertebrates. Alphaviruses that could 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 individuals 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>Jaagsiekte sheep retrovirus</i> Species of virus

Jaagsiekte sheep retrovirus (JSRV) is a betaretrovirus which is the causative agent of a contagious lung cancer in sheep, called ovine pulmonary adenocarcinoma.

<i>Orthoreovirus</i> Genus of viruses

Orthoreovirus is a genus of viruses, in the family Reoviridae, in the subfamily Spinareovirinae. Vertebrates serve as natural hosts. There are ten species in this genus. Diseases associated with this genus include mild upper respiratory tract disease, gastroenteritis, and biliary atresia. Mammalian orthoreovirus 3 induces cell death preferentially in transformed cells and therefore displays inherent oncolytic properties.

<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.

Simian foamy virus (SFV) is a species of the genus Spumavirus that belongs to the family of Retroviridae. It has been identified in a wide variety of primates, including prosimians, New World and Old World monkeys, as well as apes, and each species has been shown to harbor a unique (species-specific) strain of SFV, including African green monkeys, baboons, macaques, and chimpanzees. As it is related to the more well-known retrovirus human immunodeficiency virus (HIV), its discovery in primates has led to some speculation that HIV may have been spread to the human species in Africa through contact with blood from apes, monkeys, and other primates, most likely through bushmeat-hunting practices.

Phycodnaviridae is a family of large (100–560 kb) double-stranded DNA viruses that infect marine or freshwater eukaryotic algae. Viruses within this family have a similar morphology, with an icosahedral capsid. As of 2014, there were 33 species in this family, divided among 6 genera. This family belongs to a super-group of large viruses known as nucleocytoplasmic large DNA viruses. Evidence was published in 2014 suggesting that specific strains of Phycodnaviridae might infect humans rather than just algal species, as was previously believed. Most genera under this family enter the host cell by cell receptor endocytosis and replicate in the nucleus. Phycodnaviridae play important ecological roles by regulating the growth and productivity of their algal hosts. Algal species such Heterosigma akashiwo and the genus Chrysochromulina can form dense blooms which can be damaging to fisheries, resulting in losses in the aquaculture industry. Heterosigma akashiwo virus (HaV) has been suggested for use as a microbial agent to prevent the recurrence of toxic red tides produced by this algal species. Phycodnaviridae cause death and lysis of freshwater and marine algal species, liberating organic carbon, nitrogen and phosphorus into the water, providing nutrients for the microbial loop.

<span class="mw-page-title-main">Double-stranded RNA viruses</span> Type of virus according to Baltimore classification

Double-stranded RNA viruses are a polyphyletic group of viruses that have double-stranded genomes made of ribonucleic acid. The double-stranded genome is used as a template by the viral RNA-dependent RNA polymerase (RdRp) to transcribe a positive-strand RNA functioning as messenger RNA (mRNA) for the host cell's ribosomes, which translate it into viral proteins. The positive-strand RNA can also be replicated by the RdRp to create a new double-stranded viral genome.

<span class="mw-page-title-main">Viral shedding</span> Dissemination of mature virions from host cell

Viral shedding is the expulsion and release of virus progeny following successful reproduction during a host cell infection. Once replication has been completed and the host cell is exhausted of all resources in making viral progeny, the viruses may begin to leave the cell by several methods.

<i>Corticovirus</i> Genus of viruses

Corticovirus is a genus of viruses in the family Corticoviridae. Corticoviruses are bacteriophages; that is, their natural hosts are bacteria. The genus contains two species. The name is derived from Latin cortex, corticis. However, prophages closely related to PM2 are abundant in the genomes of aquatic bacteria, suggesting that the ecological importance of corticoviruses might be underestimated. Bacteriophage PM2 was first described in 1968 after isolation from seawater sampled from the coast of Chile.

<span class="mw-page-title-main">Syncytin-1</span> Protein-coding gene in the species Homo sapiens

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">Prokaryote</span> Unicellular organism lacking a membrane-bound nucleus

A prokaryote is a single-cell organism whose cell lacks a nucleus and other membrane-bound organelles. The word prokaryote comes from the Ancient Greek πρό 'before' and κάρυον 'nut, kernel'. In the two-empire system arising from the work of Édouard Chatton, prokaryotes were classified within the empire Prokaryota. But in the three-domain system, based upon molecular analysis, prokaryotes are divided into two domains: Bacteria and Archaea. Organisms with nuclei are placed in a third domain, Eukaryota.

<span class="mw-page-title-main">Transmissible gastroenteritis virus</span> Species of virus

Transmissible gastroenteritis virus or Transmissible gastroenteritis coronavirus (TGEV) is a coronavirus which infects pigs. It is an enveloped, positive-sense, single-stranded RNA virus which enters its host cell by binding to the APN receptor. The virus is a member of the genus Alphacoronavirus, subgenus Tegacovirus, species Alphacoronavirus 1.

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.

An endogenous viral element (EVE) is a DNA sequence derived from a virus, and present within the germline of a non-viral organism. EVEs may be entire viral genomes (proviruses), or fragments of viral genomes. They arise when a viral DNA sequence becomes integrated into the genome of a germ cell that goes on to produce a viable organism. The newly established EVE can be inherited from one generation to the next as an allele in the host species, and may even reach fixation.

<i>Pneumoviridae</i> Family of viruses

Pneumoviridae is a family of negative-strand RNA viruses in the order Mononegavirales. Humans, cattle, and rodents serve as natural hosts. Respiratory tract infections are associated with member viruses such as human respiratory syncytial virus. There are five species in the family which are divided between the genera Metapneumovirus and Orthopneumovirus. The family used to be considered as a sub-family of Paramyxoviridae, but has been reclassified as of 2016.

<span class="mw-page-title-main">Positive-strand RNA virus</span> Class of viruses in the Baltimore classification

Positive-strand RNA viruses are a group of related viruses that have positive-sense, single-stranded genomes made of ribonucleic acid. The positive-sense genome can act as messenger RNA (mRNA) and can be directly translated into viral proteins by the host cell's ribosomes. Positive-strand RNA viruses encode an RNA-dependent RNA polymerase (RdRp) which is used during replication of the genome to synthesize a negative-sense antigenome that is then used as a template to create a new positive-sense viral genome.

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. doi: 10.1016/j.cub.2020.04.060 . PMID   32442459. S2CID   218762979.
  5. ↑ 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.
  6. 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.
  7. 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.
  8. 1 2 3 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.
  9. ↑ 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.
  10. 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.
  11. ↑ 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.
  12. ↑ 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.
  13. 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.
  14. 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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