Summary: Envelope glycoprotein GP120
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Envelope glycoprotein GP120 Edit Wikipedia article
|Envelope glycoprotein 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 1988. The 120 in its name comes from its molecular weight of 120 kDa. Gp120 is essential for virus entry into cells as it plays a vital role in attachment to specific cell surface receptors. These receptors are DC-SIGN, Heparan Sulfate Proteoglycan and a specific interaction with the CD4 receptor, particularly on helper T-cells. Binding to CD4 induces the start of a cascade of conformational changes in gp120 and gp41 that lead to the fusion of the viral with the host cell membrane. Binding to CD4 is mainly electrostatic although there are van der Waals interactions and hydrogen bonds.
Gp120 is coded by the HIV env gene, which is around 2.5 kb long and codes for around 850 amino acids. The primary env product is the protein gp160, which gets cleaved to gp120 (~480 amino acids) and gp41 (~345 amino acids) in the endoplasmatic reticulum by the cellular protease furin. The crystal structure of core gp120 shows an organization with an outer domain, an inner domain with respect to its termini and a bridging sheet. Gp120 is anchored to the viral membrane, or envelope, via non-covalent bonds with the transmembrane glycoprotein, gp41. Three gp120s and gp41s combine in a trimer of heterodimers to form the envelope spike, which mediates attachment to and entry into the host cell.
Since gp120 plays a vital role in the ability of HIV-1 to enter CD4+ cells, its evolution is of particular interest. Many neutralizing antibodies bind to sites located in variable regions of gp120, so mutations in these regions will be selected for strongly. The diversity of env has been shown to increase by 1-2% per year in HIV-1 group M and the variable units are notable for rapid changes in amino acid sequence length. Increases in gp120 variability result in significantly elevated levels of viral replication, indicating an increase in viral fitness in individuals infected by diverse HIV-1 variants. Further studies have shown that variability in potential N-linked glycosylation sites (PNGSs) also result in increased viral fitness. PNGSs allow for the binding of long-chain carbohydrates to the high variability regions of gp120, so the authors hypothesize that the number of PNGSs in env might affect the fitness of the virus by providing more or less sensitivity to neutralizing antibodies. The presence of large carbohydrate chains extending from gp120 might obscure possible antibody binding sites.
The boundaries of the potential to add and eliminate PNGSs are naively explored by growing viral populations following each new infection. While the transmitting host has developed a neutralizing antibody response to gp120, the newly infected host lacks immune recognition of the virus. Sequence data shows that initial viral variants in an immunologically naïve host have few glycosylation sites and shorter exposed variable loops. This may facilitate viral ability to bind host cell receptors. As the host immune system develops antibodies against gp120, immune pressures seem to select for increased glycosylation, particularly on the exposed variable loops of gp120. Consequently, insertions in env, which confer more PNGSs on gp120 may be more tolerated by the virus as higher glycan density promotes the viral ability to evade antibodies and thus promotes higher viral fitness. In considering how much PNGS density could theoretically change, there may be an upper bound to PNGS number due to its inhibition of gp120 folding, but if the PNGS number decreases substantially, then the virus is too easily detected by neutralizing antibodies. Therefore, a stabilizing selection balance between low and high glycan densities is likely established. A lower number of bulky glycans improves viral replication efficiency and higher number on the exposed loops aids host immune evasion via disguise.
The relationship between gp120 and neutralizing antibodies is an example of Red Queen evolutionary dynamics. Continuing evolutionary adaptation is required for the viral envelope protein to maintain fitness relative to the continuing evolutionary adaptations of the host immune neutralizing antibodies, and vice versa, forming a coevolving system.
Since CD4 receptor binding is the most obvious step in HIV infection, gp120 was among the first targets of HIV vaccine research. Efforts to develop HIV vaccines targeting gp120, however, have been hampered by the chemical and structural properties of gp120, which make it difficult for antibodies to bind to it. gp120 can also easily be shed from the surface of the virus and captured by T cells due to its loose binding with gp41. A conserved region in the gp120 glycoprotein that is involved in the metastable attachment of gp120 to CD4 has been identified and targeting of invariant region has been achieved with a broadly neutralising antibody, IgG1-b12. 
NIH research published in Science reports the isolation of 3 antibodies that neutralize 90% of HIV-1 strains at the CD4bs region of gp120, potentially offering a therapeutic and vaccine strategy.  However, most antibodies that bind the CDbs region of gp120 do not neutralize HIV, and rare ones that do such as IgG1-b12 have unusual properties such as asymmetry of the Fab arms or in their positioning. Unless a gp120-based vaccine can be designed to elicit antibodies with strongly neutralizing antiviral properties, there is concern that breakthrough infection leading to humoral production of high levels of non-neutralizing antibodies targeting the CD4 binding site of gp120 is associated with faster disease progression to AIDS.
The protein gp120 is necessary during the initial binding of HIV to its target cell. Consequently, anything which binds to gp120 or its targets can physically block gp120 from binding to a cell. Only one such agent, Maraviroc, which binds the co-receptor CCR5 is currently licensed and in clinical use. No agent targeting gp120's main first cellular interaction partner, CD4, is currently licensed since interfering with such a central molecule of the immune system can cause toxic side effects, such as the anti-CD4 monoclonal antibody OKT4. Targeting gp120 itself has proven extremely difficult due to its high degree of variability and shielding. Fostemsavir (BMS-663068) is a methyl phosphate prodrug of the small molecule inhibitor BMS-626529, which prevents viral entry by binding to the viral envelope gp120 and interfering with virus attachment to the host CD4 receptor.
The HIV viral protein gp120 induces apoptosis of neuronal cells by inhibiting levels of furin and tissue plasminogen activator, enzymes responsible for converting pBDNF to mBDNF. gp120 induces mitochondrial-death proteins like caspases which may influence the upregulation of the death receptor Fas leading to apoptosis of neuronal cells, gp120 induces oxidative stress in the neuronal cells, and it is also known to activate STAT1 and induce interleukins IL-6 and IL-8 secretion in neuronal cells.
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- Zhang M, Gaschen B, Blay W, Foley B, Haigwood N, Kuiken C, Korber B (December 2004). "Tracking global patterns of N-linked glycosylation site variation in highly variable viral glycoproteins: HIV, SIV, and HCV envelopes and influenza hemagglutinin". Glycobiology. 14 (12): 1229–46. doi:10.1093/glycob/cwh106. PMID 15175256.
- Liu Y, Curlin ME, Diem K, Zhao H, Ghosh AK, Zhu H, Woodward AS, Maenza J, Stevens CE, Stekler J, Collier AC, Genowati I, Deng WZioni R, Corey L, Zhu T, Mullins JI (May 2008). "Env length and N-linked glycosylation following transmission of human immunodeficiency virus Type 1 subtype B viruses". Virology. 374 (2): 229–33. doi:10.1016/j.virol.2008.01.029. PMC . PMID 18314154.
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- Barbas CF, Björling E, Chiodi F, Dunlop N, Cababa D, Jones TM, Zebedee SL, Persson MA, Nara PL, Norrby E (October 1992). "Recombinant human Fab fragments neutralize human type 1 immunodeficiency virus in vitro". Proc. Natl. Acad. Sci. U.S.A. 89 (19): 9339–43. doi:10.1073/pnas.89.19.9339. PMC . PMID 1384050.
- Zhou T, Xu L, Dey B, Hessell AJ, Van Ryk D, Xiang SH, Yang X, Zhang MY, Zwick MB, Arthos J, Burton DR, Dimitrov DS, Sodroski J, Wyatt R, Nabel GJ, Kwong PD (2007). "Structural definition of a conserved neutralization epitope on HIV-1 gp120". Nature. 445 (7129): 732–737. doi:10.1038/nature05580. PMC . PMID 17301785.
- Pantophlet, Ralph; Ollmann Saphire, Erica; Poignard, Pascal; Parren, Paul W. H. I.; Wilson, Ian A.; Burton, Dennis R. (2003-01-01). "Fine mapping of the interaction of neutralizing and nonneutralizing monoclonal antibodies with the CD4 binding site of human immunodeficiency virus type 1 gp120". Journal of Virology. 77 (1): 642–658. doi:10.1128/jvi.77.1.642-658.2003. ISSN 0022-538X. PMC . PMID 12477867.
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- Solanki, Ashish K.; Rathore, Yogendra S.; Badmalia, Maulik D.; Dhoke, Reema R.; Nath, Samir K.; Nihalani, Deepak; Ashish (2014-12-12). "Global Shape and Ligand Binding Efficiency of the HIV-1-neutralizing Antibodies Differ from Those of Antibodies That Cannot Neutralize HIV-1". The Journal of Biological Chemistry. 289 (50): 34780–34800. doi:10.1074/jbc.M114.563486. ISSN 0021-9258. PMC . PMID 25331945.
- Chien, Peter C.; Cohen, Sandra; Kleeberger, Cynthia; Giorgi, Janis; Phair, John; Zolla-Pazner, Susan; Hioe, Catarina E. (2002-07-15). "High levels of antibodies to the CD4 binding domain of human immunodeficiency virus type 1 glycoprotein 120 are associated with faster disease progression". The Journal of Infectious Diseases. 186 (2): 205–213. doi:10.1086/341297. ISSN 0022-1899. PMID 12134256.
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- Thomas S, Mayer L, Sperber K (2009). "Mitochondria influence Fas expression in gp120-induced apoptosis of neuronal cells". Int. J. Neurosci. 119 (2): 157–65. doi:10.1080/00207450802335537. PMID 19125371.
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This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Envelope glycoprotein GP120 Provide feedback
The entry of HIV requires interaction of viral GP120 with P01730 and a chemokine receptor on the cell surface.
Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA; , Nature 1998;393:648-659.: Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. PUBMED:9641677 EPMC:9641677
External database links
This tab holds annotation information from the InterPro database.
InterPro entry IPR000777
The envelope glycoprotein Gp160 of HIV1 is cleaved into the surface protein Gp120 and the transmembrane protein Gp41. The entry of HIV requires interaction of viral Gp120 with the CD4 glycoprotein and a chemokine receptor on the cell surface [PUBMED:9641677].
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||viral envelope (GO:0019031)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
Format an alignment
We make all of our alignments available in Stockholm format. You can download them here as raw, plain text files or as gzip-compressed files.
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This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.
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This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.
|Seed source:||Pfam-B_44 (release 1.0)|
|Number in seed:||2|
|Number in full:||34|
|Average length of the domain:||385.90 aa|
|Average identity of full alignment:||49 %|
|Average coverage of the sequence by the domain:||57.89 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||18|
|Download:||download the raw HMM for this family|
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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the More....
This chart is a modified "sunburst" visualisation of the species tree for this family. It shows each node in the tree as a separate arc, arranged radially with the superkingdoms at the centre and the species arrayed around the outermost ring.
How the sunburst is generated
The tree is built by considering the taxonomic lineage of each sequence that has a match to this family. For each node in the resulting tree, we draw an arc in the sunburst. The radius of the arc, its distance from the root node at the centre of the sunburst, shows the taxonomic level ("superkingdom", "kingdom", etc). The length of the arc represents either the number of sequences represented at a given level, or the number of species that are found beneath the node in the tree. The weighting scheme can be changed using the sunburst controls.
In order to reduce the complexity of the representation, we reduce the number of taxonomic levels that we show. We consider only the following eight major taxonomic levels:
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Segments of the tree are coloured approximately according to their superkingdom. For example, archeal branches are coloured with shades of orange, eukaryotes in shades of purple, etc. The colour assignments are shown under the sunburst controls. Where space allows, the name of the taxonomic level will be written on the arc itself.
As you move your mouse across the sunburst, the current node will be highlighted. In the top section of the controls panel we show a summary of the lineage of the currently highlighed node. If you pause over an arc, a tooltip will be shown, giving the name of the taxonomic level in the title and a summary of the number of sequences and species below that node in the tree.
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Some species in the taxonomic tree may not have one or more of the main eight levels that we display. For example, Bos taurus is not assigned an order in the NCBI taxonomic tree. In such cases we mark the omitted level with, for example, "No order", in both the tooltip and the lineage summary.
Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
So that these nodes are not simply omitted from the sunburst tree, we group them together in a separate branch (or segment of the sunburst tree). Since we cannot determine the lineage for these unmapped species, we show all levels between the superkingdom and the species as "uncategorised".
Since we reduce the species tree to only the eight main taxonomic levels, sequences that are mapped to the sub-species level in the tree would not normally be shown. Rather than leave out these species, we map them instead to their parent species. So, for example, for sequences belonging to one of the Vibrio cholerae sub-species in the NCBI taxonomy, we show them instead as belonging to the species Vibrio cholerae.
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For large species trees, you may see blank regions in the outer layers of the sunburst. These occur when there are large numbers of arcs to be drawn in a small space. If an arc is less than approximately one pixel wide, it will not be drawn and the space will be left blank. You may still be able to get some information about the species in that region by moving your mouse across the area, but since each arc will be very small, it will be difficult to accurately locate a particular species.
The tree shows the occurrence of this domain across different species. More...
We show the species tree in one of two ways. For smaller trees we try to show an interactive representation, which allows you to select specific nodes in the tree and view them as an alignment or as a set of Pfam domain graphics.
Unfortunately we have found that there are problems viewing the interactive tree when the it becomes larger than a certain limit. Furthermore, we have found that Internet Explorer can become unresponsive when viewing some trees, regardless of their size. We therefore show a text representation of the species tree when the size is above a certain limit or if you are using Internet Explorer to view the site.
If you are using IE you can still load the interactive tree by clicking the "Generate interactive tree" button, but please be aware of the potential problems that the interactive species tree can cause.
For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
We also count the number of unique sequences on which each domain is found, which is shown in green. Note that a domain may appear multiple times on the same sequence, leading to the difference between these two numbers.
Finally, we group sequences from the same organism according to the NCBI code that is assigned by UniProt, allowing us to count the number of distinct sequences on which the domain is found. This value is shown in the pink boxes.
We use the NCBI species tree to group organisms according to their taxonomy and this forms the structure of the displayed tree. Note that in some cases the trees are too large (have too many nodes) to allow us to build an interactive tree, but in most cases you can still view the tree in a plain text, non-interactive representation. Those species which are represented in the seed alignment for this domain are highlighted.
You can use the tree controls to manipulate how the interactive tree is displayed:
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There are 5 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the GP120 domain has been found. There are 604 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.
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