Membrane fusion proteins (not to be confused with chimeric or

fusion protein Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this '' fusion gene'' ...

s) are proteins that cause fusion of biological membranes. Membrane fusion is critical for many biological processes, especially in eukaryotic development and

viral entry 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 variati ...

. Fusion proteins can originate from genes encoded by infectious

enveloped viruses 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. Numerous human pathogenic viruses in circulation are encas ...

, ancient

retroviruses A retrovirus is a type of virus that inserts a DNA copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptas ...

integrated into the host genome, or solely by the host genome. 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).

Fusion in eukaryotes

Eukaryotic genomes contain several

gene families A gene family is a set of several similar genes, formed by duplication of a single original gene, and generally with similar biochemical functions. One such family are the genes for human hemoglobin subunits; the ten genes are in two clusters on ...

, 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 Syncytiotrophoblast (from the Greek 'syn'- "together"; 'cytio'- "of cells"; 'tropho'- "nutrition"; 'blast'- "bud") is the epithelial covering of the highly vascular embryonic placental villi, which invades the wall of the uterus to establish nu ...

formation, and neurodevelopment. Fusion pathways are also involved in the development of

musculoskeletal The human musculoskeletal system (also known as the human locomotor system, and previously the activity system) is an organ system that gives humans the ability to move using their muscular and skeletal systems. The musculoskeletal system prov ...

and

nervous system In biology, the nervous system is the highly complex part of an animal that coordinates its actions and sensory information by transmitting signals to and from different parts of its body. The nervous system detects environmental changes ...

tissues.

Vesicle fusion Vesicle fusion is the merging of a vesicle with other vesicles or a part of a cell membrane. In the latter case, it is the end stage of secretion from secretory vesicles, where their contents are expelled from the cell through exocytosis. Vesicles c ...

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 Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...

relatives like

Heimdallarchaeota Asgard or Asgardarchaeota is a proposed superphylum consisting of a group of archaea that includes Lokiarchaeota, Thorarchaeota, Odinarchaeota, and Heimdallarchaeota. It appears the eukaryotes emerged within the Asgard, in a branch containing ...

. * VAMP

Retroviral

These proteins originate from the ''env'' gene of endogenous retroviruses. They are domesticated viral class I fusion proteins. * Syncytins are responsible for structures of the

placenta The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate mate ...

. **

Syncytin-1 Syncytin-1 also known as enverin is a protein found in humans and other primates that is encoded by the ERVW-1 gene ( endogenous retrovirus group W envelope member 1). Syncytin-1 is a cell-cell fusion protein whose function is best characterized ...

** Syncytin-2 *

ERV3 HERV-R_7q21.2 provirus ancestral envelope (Env) polyprotein is a protein that in humans is encoded by the ''ERV3'' gene. Function The human genome includes many retroelements including the human endogenous retroviruses (HERVs), which compose ...

is not functional in humans

HAP2 family

HAP2 is a domesticated viral class II fusion protein found in diverse eukaryotes including ''

Toxoplasma ''Toxoplasma gondii'' () is an obligate intracellular parasitic protozoan (specifically an apicomplexan) that causes toxoplasmosis. Found worldwide, ''T. gondii'' is capable of infecting virtually all warm-blooded animals, but felids, such as ...

'',

vascular plants Vascular plants (), also called tracheophytes () or collectively Tracheophyta (), form a large group of land plants ( accepted known species) that have lignified tissues (the xylem) for conducting water and minerals throughout the plant. They ...

, and fruit flies. This protein is essential for

gamete A gamete (; , ultimately ) is a haploid cell that fuses with another haploid cell during fertilization in organisms that reproduce sexually. Gametes are an organism's reproductive cells, also referred to as sex cells. In species that produce ...

fusion in these organisms.

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 A syncytium (; plural syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell which can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleu ...

, or (2) be incorporated into a budding

virion A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's ...

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 factor Host factor (sometimes known as risk factor) is a medicine, medical term referring to the traits of an individual person or animal that affect susceptibility to disease, especially in comparison to other individuals. The term arose in the context of ...

s. There are four groups of fusion proteins categorized by their structure and mechanism of fusion.

Class I

Class I fusion proteins resemble

influenzavirus ''Orthomyxoviridae'' (from Greek language, Greek ὀρθός, ''orthós'' 'straight' + μύξα, ''mýxa'' 'mucus') is a family of negative-sense single-stranded RNA virus, negative-sense RNA viruses. It includes seven genus, genera: ''Influenza ...

hemagglutinin In molecular biology, hemagglutinins (or ''haemagglutinin'' in British English) (from the Greek , 'blood' + Latin , 'glue') are receptor-binding membrane fusion glycoproteins produced by viruses in the '' Paramyxoviridae'' family. Hemagglutinins a ...

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.

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.

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.

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 ''Reoviridae'' is a family of double-stranded RNA viruses. Member viruses have a wide host range, including vertebrates, invertebrates, plants, protists and fungi. They lack lipid envelopes and package their segmented genome within multi-layered ...

, which are non-enveloped viruses and are specialized for cell-cell rather than virus-cell fusion, forming

syncytia A syncytium (; plural syncytia; from Greek: σύν ''syn'' "together" and κύτος ''kytos'' "box, i.e. cell") or symplasm is a multinucleate cell which can result from multiple cell fusions of uninuclear cells (i.e., cells with a single nucleus) ...

. They are the only known membrane fusion proteins found in non-enveloped viruses.

Examples

References

External links

* {{Membrane proteins Membrane proteins