''Env'' is a viral gene that encodes the protein forming the

viral envelope 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 en ...

. The expression of the ''env'' gene enables

retrovirus 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. After invading a host cell's cytoplasm, the virus uses its own reverse transcriptase e ...

es to target and attach to specific cell types, and to infiltrate the target

cell membrane The cell membrane (also known as the plasma membrane or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of a cell from the outside environment (the extr ...

. Analysis of the structure and sequence of several different ''env'' genes suggests that Env proteins are type 1 fusion machines. Type 1 fusion machines initially bind a receptor on the target cell surface, which triggers a

conformational change In biochemistry, a conformational change is a change in the shape of a macromolecule, often induced by environmental factors. A macromolecule is usually flexible and dynamic. Its shape can change in response to changes in its environment or othe ...

, allowing for binding of the

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'' ...

. The

fusion peptide 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 ...

inserts itself in the host cell membrane and brings the host cell membrane very close to the viral membrane to facilitate membrane fusion. While there are significant differences in sequence of the ''env'' gene between

es, the gene is always located downstream of ''

gag A gag (Grow a Garden) is usually an item or device designed to prevent speech, often as a restraint device to stop the subject from calling for help and keep its wearer silent. This is usually done by blocking the mouth, partially or completely ...

'', ''pro'', and '' pol''. The ''env''

mRNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein. mRNA is ...

must be

spliced Spliced may refer to: *Spliced, the result of rope splicing Rope splicing in ropework is the forming of a semi-permanent joint between two ropes or two parts of the same rope by partly untwisting and then interweaving their strands. Splices ca ...

for expression. The mature product of the ''env'' gene is the viral spike protein, which has two main parts: the surface protein (SU) and the transmembrane protein (TM). The

tropism In biology, a tropism is a phenomenon indicating the growth or turning movement of an organism, usually a plant, in response to an environmental stimulus (physiology), stimulus. In tropisms, this response is dependent on the direction of the s ...

of the virus is determined by the SU protein domain because it is responsible for the receptor-binding function of the virus. The SU domain therefore determines the specificity of the virus for a single receptor molecule.

Physical structure

Oligomerization

The retroviral glycoproteins are oligomeric complexes that are composed of SU-TM

heterodimer In biochemistry, a protein dimer is a macromolecular complex or multimer formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ...

s, which are made in the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

after the translation of the glycosylated Env precursor. The arrangement of these heterodimers determines the 3D structure of the knobbed spike on the viral surface. The Env proteins of the Avian Sarcoma and Leukosis virus ( ASLV) and the Murine Leukemia Virus ( MLV) are both trimers of SU-TM heterodimers. The Env protein of Human Immunodeficiency Virus (

HIV The human immunodeficiency viruses (HIV) are two species of '' Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the im ...

) also has a trimeric structure of heterodimers. It is believed that the intracellular transport of the nascent protein depends, to some extent, on the oligomerization of Env precursors, which allows hydrophobic sequences to be buried inside the protein structure. This oligomerization has also been implicated in fusion initiation with the membrane of the target cell.

Post-translational modification

Env can be modified by the addition of mannose-rich oligosaccharides, a process that takes place in the rough endoplasmic reticulum and is carried out by the enzymes of the host cell. Cotranslational

glycosylation Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...

take place at the asparagine in the Asn-X-Ser or Asn-X-Thr motifs. Different retroviruses vary widely in N-linked glycosylation sites:

HIV-1 The subtypes of HIV include two main subtypes, known as HIV type 1 (HIV-1) and HIV type 2 (HIV-2). These subtypes have distinct genetic differences and are associated with different epidemiological patterns and clinical characteristics. HIV-1 e ...

can have as many as 30 sites glycosylated, 25 of which reside in

gp120 Envelope glycoprotein GP120 (or gp120) is a glycoprotein exposed on the surface of the HIV envelope. It was discovered by Professors Tun-Hou Lee and Myron "Max" Essex of the Harvard School of Public Health in 1984. The 120 in its name comes f ...

. At the other end of the spectrum, MMTV (

Mouse Mammary Tumor Virus Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTL viruses, HI viruses, and BLV. It belongs to the genus ''Betaretrovirus''. MMTV was formerly known as Bittner virus, and previously the "milk factor", referring to t ...

has only 4 sites for oligosaccharide addition (two on gp52 and two on gp37). The addition of oligosaccharides is believed to play a role in the proper folding of Env, presumably by stabilizing the protein structure. Without proper folding, protein transport and function can be severely compromised. The importance of glycosylation of Env in HIV-1 was ascertained by synthesizing the glycoprotein in the presence of a glycosylation inhibitor,

tunicamycin Tunicamycin is a mixture of homologous nucleoside antibiotics that inhibits the UDP-HexNAc: polyprenol-P HexNAc-1-P family of enzymes. In eukaryotes, this includes the enzyme GlcNAc phosphotransferase (GPT), which catalyzes the transfer of ' ...

. The synthesized protein was incorrectly folded and incapable of binding

CD4 In molecular biology, CD4 (cluster of differentiation 4) is a glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). CD4 is found on the surface of immune cells such as helper T cells, monocytes, macrophages, and dendritic c ...

. Receptor binding was only minimally affected, however, when the secreted ''env'' product was enzymatically deglycosylated.

In HIV

The ''env'' gene codes for the gp160 protein which forms a homotrimer, and is cleaved into gp120 and gp41 by the host cell

protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...

, furin. To form an active fusion protein, SU gp120 and TM gp41 polypeptides remain non-covalently bound together, but this interaction is often not stable, leading to shed, soluble gp120 and membrane-bound, gp41 'stumps'. Separately, cleavage by furin is inefficient, and virions often are released with inactive, uncleaved gp160. Because of the high prevalence of these inactive forms, the immune system often produces

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

which target inactive gp160, rather than active forms of the envelope protein. ''See Replication cycle of HIV.'' ''Env'' expression is regulated by the gene product of ''

rev Rev, REV or Rév may refer to: Abbreviations Rev. * Rev., an abbreviation for revolution, as in Revolutions per minute * Rev., an abbreviation for the religious style The Reverend * Rev., the abbreviation for Runtime Revolution, a development en ...

''. Experimental deletion of ''rev'' resulted in the inability to detect the Env protein and levels of ''env'' mRNA in the cell cytoplasm were significantly diminished. However, when total cellular RNA was analyzed, ''env'' RNA totals were not significantly different in the presence and absence of ''rev'' coexpression. It was found that without ''rev'' expression, there was a marked increase in nuclear ''env'' RNA, which suggests that ''rev'' plays an important role in the nuclear export of ''env'' mRNA. The role of ''rev'' was further elucidated when it was found that ''rev'' acts

in trans In the field of molecular biology, ''trans''-acting (''trans''-regulatory, ''trans''-regulation), in general, means "acting from a different molecule" (''i.e.'', intermolecular). It may be considered the opposite of ''cis''-acting (''cis''-regulat ...

to target a specific sequence present in the ''env'' gene of HIV-1 to initiate export of incompletely spliced HIV-1 RNA from the nucleus.

gp120

Exposed on the surface of the viral envelope, the

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...

gp120 binds to the

receptor Receptor may refer to: * Sensory receptor, in physiology, any neurite structure that, on receiving environmental stimuli, produces an informative nerve impulse *Receptor (biochemistry), in biochemistry, a protein molecule that receives and respond ...

on any target cell that has such a receptor, particularly the

helper T-cell The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...

. Strains of HIV-1 have been isolated that are able to enter host cells that are CD4 negative. This CD4-independence is associated with spontaneous mutation in the ''env'' gene. The presence of a

co-receptor A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate Ligand (biochemistry), ligand recognition and initiate biological processes, such as entry of a pathogen into a host ...

, CXCR₄, is sufficient for this mutant strain to infect human cells. The strain with this

phenotype In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...

was found to have seven mutations in the sequence coding for gp120 and it is proposed that these mutations induce conformational changes in gp120 that allow the virus to directly interact with the co-receptor. Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of

HIV vaccine The HIV vaccine is a combination antiretroviral vaccine that protects people who are HIV-negative and at high risk of infection from HIV infection. According to the WHO, "every minute, one person in the world dies from AIDS-related causes." Ac ...

research. These efforts have been hampered by the fusion mechanism used by HIV, which makes neutralization by antibodies extremely difficult. Prior to binding the host cell, gp120 remains effectively hidden from antibodies because it is buried in the protein and shielded by sugars. Gp120 is only exposed when in close proximity to a host cell and the space between the viral and host cell membranes is small enough to sterically hinder the binding of antibodies.

gp41

The glycoprotein gp41 is non-

covalently A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atoms ...

bound to gp120, and provides the second step by which HIV enters the cell. It is originally buried within the viral envelope, but when gp120 binds to a CD4 receptor, gp120 changes its conformation causing gp41 to become exposed, where it can assist in fusion with the host cell.

Fusion inhibitor Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a Cell (biology), cell, for example, by blocking a Receptor (biochemistry), receptor. Entry inhibitors are used to treat condition ...

drugs such as

enfuvirtide Enfuvirtide (International Nonproprietary Name, INN), sold under the brand name Fuzeon, is an HIV fusion inhibitor, the first of a class of antiretroviral drugs used in combination therapy for the treatment of AIDS/HIV. Medical uses Enfuvirti ...

block the fusion process by binding to gp41.

Env in MMTV

The Mouse Mammary Tumor Virus (

MMTV Mouse mammary tumor virus (MMTV) is a milk-transmitted retrovirus like the HTL viruses, HI viruses, and BLV. It belongs to the genus ''Betaretrovirus''. MMTV was formerly known as Bittner virus, and previously the "milk factor", referring to t ...

) ''env'' gene codes for a polyprotein gp70 () that is cleaved to yield the surface (SU) and transmembrane (TM) Env products. Gp52 is the SU subunit in MMTV and gp36 is the TM subunit. Gp52 is a 52,000-dalton glycoprotein and gp36 is a 36,000-dalton glycoprotein. MMTV Env is of particular interest to researchers because of the discovery that it encodes an immunoreceptor tyrosine-based activation motif (I TAM) that has been shown to transform human and murine mammary cell in culture. This ITAM depolarizes

epithelial Epithelium or epithelial tissue is a thin, continuous, protective layer of cells with little extracellular matrix. An example is the epidermis, the outermost layer of the skin. Epithelial ( mesothelial) tissues line the outer surfaces of man ...

acinar structures, thereby changing the phenotype of the cells and causing them to become cancerous.

Env in ASLV

Subgroup A

Avian Sarcoma and Leukosis Viruses ( ASLV) have ten subgroups (A through J). The envelope glycoprotein of subgroup A is called EnvA and its ''env'' gene codes for precursor protein known as Pr95. This precursor is cleaved by host cell enzymes to yield the surface protein subunit, gp85, and the transmembrane protein subunit, gp37, which heterodimerize and then form a trimer. The virus cannot infect cells before the processing of the envelope precursor protein is completed. For the virus to penetrate the cytosol of a host cell, a low pH is necessary.

Env in MLV

The ''env'' gene of

Murine Leukemia Virus The murine leukemia viruses (MLVs or MuLVs) are retroviruses named for their ability to cause cancer in murine (mouse) hosts. Some MLVs may infect other vertebrates. MLVs include both exogenous and endogenous viruses. Replicating MLVs have a p ...

(MLV) codes for the 71,000-dalton glycoprotein, gp71. This membrane receptor was isolated from Rauscher murine leukemia virus (R-MuLV).

Env in mammalian evolution

The retroviral protein env has been captured multiple times during

mammalian evolution The evolution of mammals has passed through many stages since the first appearance of their synapsid ancestors in the Pennsylvanian (geology), Pennsylvanian sub-period of the late Carboniferous period. By the mid-Triassic, there were many synaps ...

and is expressed in placental tissue, where it facilitates fusion of fetal and maternal cells. The protein is called

syncytin 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 ...

in mammals.Nova. 2016. Endogenous retroviruses. Retrieved from https://www.pbs.org/wgbh/nova/article/endogenous-retroviruses/

References

External links

* * {{Viral proteins Viral structural proteins