P04588 · POL_HV1MA

Function

function

Gag-Pol polyprotein

Mediates, with Gag polyprotein, the essential events in virion assembly, including binding the plasma membrane, making the protein-protein interactions necessary to create spherical particles, recruiting the viral Env proteins, and packaging the genomic RNA via direct interactions with the RNA packaging sequence (Psi). Gag-Pol polyprotein may regulate its own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, the polyprotein would promote translation, whereas at high concentration, the polyprotein would encapsidate genomic RNA and then shut off translation.

Matrix protein p17

Targets the polyprotein to the plasma membrane via a multipartite membrane-binding signal, that includes its myristoylated N-terminus. Matrix protein is part of the pre-integration complex. Implicated in the release from host cell mediated by Vpu. Binds to RNA.

Capsid protein p24

Forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. Most core are conical, with only 7% tubular. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry (By similarity).
Host restriction factors such as TRIM5-alpha or TRIMCyp bind retroviral capsids and cause premature capsid disassembly, leading to blocks in reverse transcription. Capsid restriction by TRIM5 is one of the factors which restricts HIV-1 to the human species. Host PIN1 apparently facilitates the virion uncoating. On the other hand, interactions with PDZD8 or CYPA stabilize the capsid

Nucleocapsid protein p7

Encapsulates and protects viral dimeric unspliced genomic RNA (gRNA). Binds these RNAs through its zinc fingers. Acts as a nucleic acid chaperone which is involved in rearangement of nucleic acid secondary structure during gRNA retrotranscription. Also facilitates template switch leading to recombination. As part of the polyprotein, participates in gRNA dimerization, packaging, tRNA incorporation and virion assembly.

Protease

Aspartyl protease that mediates proteolytic cleavages of Gag and Gag-Pol polyproteins during or shortly after the release of the virion from the plasma membrane. Cleavages take place as an ordered, step-wise cascade to yield mature proteins. This process is called maturation. Displays maximal activity during the budding process just prior to particle release from the cell. Also cleaves Nef and Vif, probably concomitantly with viral structural proteins on maturation of virus particles. Hydrolyzes host EIF4GI and PABP1 in order to shut off the capped cellular mRNA translation. The resulting inhibition of cellular protein synthesis serves to ensure maximal viral gene expression and to evade host immune response. Also mediates cleavage of host YTHDF3. Mediates cleavage of host CARD8, thereby activating the CARD8 inflammasome, leading to the clearance of latent HIV-1 in patient CD4+ T-cells after viral reactivation; in contrast, HIV-1 can evade CARD8-sensing when its protease remains inactive in infected cells prior to viral budding (By similarity).

Reverse transcriptase/ribonuclease H

Multifunctional enzyme that converts the viral RNA genome into dsDNA in the cytoplasm, shortly after virus entry into the cell. This enzyme displays a DNA polymerase activity that can copy either DNA or RNA templates, and a ribonuclease H (RNase H) activity that cleaves the RNA strand of RNA-DNA heteroduplexes in a partially processive 3' to 5' endonucleasic mode. Conversion of viral genomic RNA into dsDNA requires many steps. A tRNA3-Lys binds to the primer-binding site (PBS) situated at the 5'-end of the viral RNA. RT uses the 3' end of the tRNA primer to perform a short round of RNA-dependent minus-strand DNA synthesis. The reading proceeds through the U5 region and ends after the repeated (R) region which is present at both ends of viral RNA. The portion of the RNA-DNA heteroduplex is digested by the RNase H, resulting in a ssDNA product attached to the tRNA primer. This ssDNA/tRNA hybridizes with the identical R region situated at the 3' end of viral RNA. This template exchange, known as minus-strand DNA strong stop transfer, can be either intra- or intermolecular. RT uses the 3' end of this newly synthesized short ssDNA to perform the RNA-dependent minus-strand DNA synthesis of the whole template. RNase H digests the RNA template except for two polypurine tracts (PPTs) situated at the 5'-end and near the center of the genome. It is not clear if both polymerase and RNase H activities are simultaneous. RNase H probably can proceed both in a polymerase-dependent (RNA cut into small fragments by the same RT performing DNA synthesis) and a polymerase-independent mode (cleavage of remaining RNA fragments by free RTs). Secondly, RT performs DNA-directed plus-strand DNA synthesis using the PPTs that have not been removed by RNase H as primers. PPTs and tRNA primers are then removed by RNase H. The 3' and 5' ssDNA PBS regions hybridize to form a circular dsDNA intermediate. Strand displacement synthesis by RT to the PBS and PPT ends produces a blunt ended, linear dsDNA copy of the viral genome that includes long terminal repeats (LTRs) at both ends.

Integrase

Catalyzes viral DNA integration into the host chromosome, by performing a series of DNA cutting and joining reactions. This enzyme activity takes place after virion entry into a cell and reverse transcription of the RNA genome in dsDNA. The first step in the integration process is 3' processing. This step requires a complex comprising the viral genome, matrix protein, Vpr and integrase. This complex is called the pre-integration complex (PIC). The integrase protein removes 2 nucleotides from each 3' end of the viral DNA, leaving recessed CA OH's at the 3' ends. In the second step, the PIC enters cell nucleus. This process is mediated through integrase and Vpr proteins, and allows the virus to infect a non dividing cell. This ability to enter the nucleus is specific of lentiviruses, other retroviruses cannot and rely on cell division to access cell chromosomes. In the third step, termed strand transfer, the integrase protein joins the previously processed 3' ends to the 5' ends of strands of target cellular DNA at the site of integration. The 5'-ends are produced by integrase-catalyzed staggered cuts, 5 bp apart. A Y-shaped, gapped, recombination intermediate results, with the 5'-ends of the viral DNA strands and the 3' ends of target DNA strands remaining unjoined, flanking a gap of 5 bp. The last step is viral DNA integration into host chromosome. This involves host DNA repair synthesis in which the 5 bp gaps between the unjoined strands are filled in and then ligated. Since this process occurs at both cuts flanking the HIV genome, a 5 bp duplication of host DNA is produced at the ends of HIV-1 integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration.

Miscellaneous

Reverse transcriptase/ribonuclease H

Error-prone enzyme that lacks a proof-reading function. High mutations rate is a direct consequence of this characteristic. RT also displays frequent template switching leading to high recombination rate. Recombination mostly occurs between homologous regions of the two copackaged RNA genomes. If these two RNA molecules derive from different viral strains, reverse transcription will give rise to highly recombinated proviral DNAs.
HIV-1 lineages are divided in three main groups, M (for Major), O (for Outlier), and N (for New, or Non-M, Non-O). The vast majority of strains found worldwide belong to the group M. Group O seems to be endemic to and largely confined to Cameroon and neighboring countries in West Central Africa, where these viruses represent a small minority of HIV-1 strains. The group N is represented by a limited number of isolates from Cameroonian persons. The group M is further subdivided in 9 clades or subtypes (A to D, F to H, J and K).
Resistance to inhibitors associated with mutations are observed both in viral protease and in reverse transcriptase. Most of the time, single mutations confer only a modest reduction in drug susceptibility. Combination of several mutations is usually required to develop a high-level drug resistance. These mutations are predominantly found in clade B viruses and not in other genotypes. They are listed in the clade B representative isolate HXB2 (AC P04585).

Catalytic activity

Cofactor

Protein has several cofactor binding sites:
Mg2+ (UniProtKB | Rhea| CHEBI:18420 )

Note: Binds 2 magnesium ions for reverse transcriptase polymerase activity.
Mg2+ (UniProtKB | Rhea| CHEBI:18420 )

Note: Binds 2 magnesium ions for ribonuclease H (RNase H) activity. Substrate-binding is a precondition for magnesium binding.
Mg2+ (UniProtKB | Rhea| CHEBI:18420 )

Note: Magnesium ions are required for integrase activity. Binds at least 1, maybe 2 magnesium ions.

Activity regulation

Protease: The viral protease is inhibited by many synthetic protease inhibitors (PIs), such as amprenavir, atazanavir, indinavir, loprinavir, nelfinavir, ritonavir and saquinavir. Use of protease inhibitors in tritherapy regimens permit more ambitious therapeutic strategies. Reverse transcriptase/ribonuclease H: RT can be inhibited either by nucleoside RT inhibitors (NRTIs) or by non nucleoside RT inhibitors (NNRTIs). NRTIs act as chain terminators, whereas NNRTIs inhibit DNA polymerization by binding a small hydrophobic pocket near the RT active site and inducing an allosteric change in this region. Classical NRTIs are abacavir, adefovir (PMEA), didanosine (ddI), lamivudine (3TC), stavudine (d4T), tenofovir (PMPA), zalcitabine (ddC), and zidovudine (AZT). Classical NNRTIs are atevirdine (BHAP U-87201E), delavirdine, efavirenz (DMP-266), emivirine (I-EBU), and nevirapine (BI-RG-587). The tritherapies used as a basic effective treatment of AIDS associate two NRTIs and one NNRTI.

Features

Showing features for site, active site, binding site, dna binding.

TypeIDPosition(s)Description
Site138-139Cleavage; by viral protease
Site227-228Cis/trans isomerization of proline peptide bond; by human PPIA/CYPA
Site369-370Cleavage; by viral protease
Site383-384Cleavage; by viral protease
Site438-439Cleavage; by viral protease
Site446-447Cleavage; by viral protease
Site493-494Cleavage; by viral protease
Active site518For protease activity; shared with dimeric partner
Site592-593Cleavage; by viral protease
Binding site702Mg2+ 1 (UniProtKB | ChEBI); catalytic; for reverse transcriptase activity
Binding site777Mg2+ 1 (UniProtKB | ChEBI); catalytic; for reverse transcriptase activity
Binding site778Mg2+ 1 (UniProtKB | ChEBI); catalytic; for reverse transcriptase activity
Site993Essential for RT p66/p51 heterodimerization
Site1006Essential for RT p66/p51 heterodimerization
Site1032-1033Cleavage; by viral protease; partial
Binding site1035Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Binding site1070Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Binding site1090Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Binding site1141Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Site1152-1153Cleavage; by viral protease
Binding site1164Zn2+ (UniProtKB | ChEBI)
Binding site1168Zn2+ (UniProtKB | ChEBI)
Binding site1192Zn2+ (UniProtKB | ChEBI)
Binding site1195Zn2+ (UniProtKB | ChEBI)
Binding site1216Mg2+ 3 (UniProtKB | ChEBI); catalytic; for integrase activity
Binding site1268Mg2+ 3 (UniProtKB | ChEBI); catalytic; for integrase activity
Binding site1304Mg2+ 3 (UniProtKB | ChEBI); catalytic; for integrase activity
DNA binding1375-1422Integrase-type

GO annotations

AspectTerm
Cellular Componenthost cell
Cellular Componenthost cell nucleus
Cellular Componenthost cell plasma membrane
Cellular Componenthost multivesicular body
Cellular Componentmembrane
Cellular Componentviral nucleocapsid
Cellular Componentvirion membrane
Molecular Functionaspartic-type endopeptidase activity
Molecular FunctionDNA binding
Molecular FunctionDNA-directed DNA polymerase activity
Molecular Functionexoribonuclease H activity
Molecular Functionlipid binding
Molecular FunctionRNA stem-loop binding
Molecular FunctionRNA-directed DNA polymerase activity
Molecular FunctionRNA-DNA hybrid ribonuclease activity
Molecular Functionstructural molecule activity
Molecular Functionzinc ion binding
Biological ProcessDNA integration
Biological ProcessDNA recombination
Biological Processestablishment of integrated proviral latency
Biological Processproteolysis
Biological Processsymbiont entry into host cell
Biological Processsymbiont-mediated activation of host apoptosis
Biological Processsymbiont-mediated suppression of host gene expression
Biological Processviral genome integration into host DNA
Biological Processviral penetration into host nucleus
Biological Processviral translational frameshifting

Keywords

Protein family/group databases

Names & Taxonomy

Protein names

Gene names

    • Name
      gag-pol

Organism names

Accessions

  • Primary accession
    P04588
  • Secondary accessions
    • Q79582

Proteomes

Subcellular Location

Gag-Pol polyprotein

Host cell membrane ; Lipid-anchor
Note: These locations are linked to virus assembly sites. The main location is the cell membrane, but under some circumstances, late endosomal compartments can serve as productive sites for virion assembly.

Matrix protein p17

Virion membrane ; Lipid-anchor
Host nucleus
Host cytoplasm

Capsid protein p24

Virion

Nucleocapsid protein p7

Virion

Reverse transcriptase/ribonuclease H

Virion

Integrase

Virion
Host nucleus
Note: Nuclear at initial phase, cytoplasmic at assembly.

Keywords

Phenotypes & Variants

Keywords

PTM/Processing

Features

Showing features for initiator methionine, lipidation, chain, modified residue, peptide.

TypeIDPosition(s)Description
Initiator methionine1Removed; by host
Lipidation2N-myristoyl glycine; by host
ChainPRO_00000423852-138Matrix protein p17
ChainPRO_00002612702-1440Gag-Pol polyprotein
Modified residue138Phosphotyrosine; by host
ChainPRO_0000042386139-369Capsid protein p24
PeptidePRO_0000042387370-383Spacer peptide 1
ChainPRO_0000042388384-438Nucleocapsid protein p7
PeptidePRO_0000246719439-446Transframe peptide
ChainPRO_0000042389447-493p6-pol
ChainPRO_0000038659494-592Protease
ChainPRO_0000042391593-1032p51 RT
ChainPRO_0000042390593-1152Reverse transcriptase/ribonuclease H
ChainPRO_00000423921033-1152p15
ChainPRO_00000423931153-1440Integrase

Post-translational modification

Gag-Pol polyprotein

Specific enzymatic cleavages by the viral protease yield mature proteins. The protease is released by autocatalytic cleavage. The polyprotein is cleaved during and after budding, this process is termed maturation. Proteolytic cleavage of p66 RT removes the RNase H domain to yield the p51 RT subunit. Nucleocapsid protein p7 might be further cleaved after virus entry.

Matrix protein p17

Tyrosine phosphorylated presumably in the virion by a host kinase. Phosphorylation is apparently not a major regulator of membrane association.

Capsid protein p24

Phosphorylated possibly by host MAPK1; this phosphorylation is necessary for Pin1-mediated virion uncoating.

Nucleocapsid protein p7

Methylated by host PRMT6, impairing its function by reducing RNA annealing and the initiation of reverse transcription.

Keywords

Interaction

Subunit

Matrix protein p17

Homotrimer; further assembles as hexamers of trimers (By similarity).
Interacts with gp41 (via C-terminus) (By similarity).
Interacts with host CALM1; this interaction induces a conformational change in the Matrix protein, triggering exposure of the myristate group (By similarity).
Interacts with host AP3D1; this interaction allows the polyprotein trafficking to multivesicular bodies during virus assembly (By similarity).
Part of the pre-integration complex (PIC) which is composed of viral genome, matrix protein, Vpr and integrase (By similarity).

Capsid protein p24

Homodimer; the homodimer further multimerizes as homohexamers or homopentamers. Interacts with human PPIA/CYPA (By similarity); This interaction stabilizes the capsid. Interacts with human NUP153 (By similarity).
Interacts with host PDZD8; this interaction stabilizes the capsid (By similarity).
Interacts with monkey TRIM5; this interaction destabilizes the capsid (By similarity).

Protease

Homodimer, whose active site consists of two apposed aspartic acid residues.

Reverse transcriptase/ribonuclease H

Heterodimer of p66 RT and p51 RT (RT p66/p51) (By similarity).
Heterodimerization of RT is essential for DNA polymerase activity (By similarity).
The overall folding of the subdomains is similar in p66 RT and p51 RT but the spatial arrangements of the subdomains are dramatically different (By similarity).

Integrase

Homotetramer; may further associate as a homohexadecamer (By similarity).
Part of the pre-integration complex (PIC) which is composed of viral genome, matrix protein, Vpr and integrase. Interacts with human SMARCB1/INI1 and human PSIP1/LEDGF isoform 1. Interacts with human KPNA3; this interaction might play a role in nuclear import of the pre-integration complex (By similarity).
Interacts with human NUP153; this interaction might play a role in nuclear import of the pre-integration complex (By similarity).

Structure

Family & Domains

Features

Showing features for region, motif, zinc finger, domain.

TypeIDPosition(s)Description
Region7-31Interaction with Gp41
Region8-43Interaction with host CALM1
Region12-19Interaction with host AP3D1
Region14-33Interaction with membrane phosphatidylinositol 4,5-bisphosphate and RNA
Motif16-22Nuclear export signal
Motif26-32Nuclear localization signal
Region73-77Interaction with membrane phosphatidylinositol 4,5-bisphosphate
Region195-233Interaction with human PPIA/CYPA and NUP153
Region283-369Dimerization/Multimerization of capsid protein p24
Zinc finger396-413CCHC-type 1
Zinc finger417-434CCHC-type 2
Region494-498Dimerization of protease
Domain513-582Peptidase A2
Region542-548Dimerization of protease
Region581-593Dimerization of protease
Domain636-826Reverse transcriptase
Region819-827RT 'primer grip'
Motif990-1006Tryptophan repeat motif
Domain1026-1149RNase H type-1
Zinc finger1155-1196Integrase-type
Domain1206-1356Integrase catalytic

Domain

Reverse transcriptase/ribonuclease H

RT is structured in five subdomains: finger, palm, thumb, connection and RNase H. Within the palm subdomain, the 'primer grip' region is thought to be involved in the positioning of the primer terminus for accommodating the incoming nucleotide. The RNase H domain stabilizes the association of RT with primer-template.

Reverse transcriptase/ribonuclease H

The tryptophan repeat motif is involved in RT p66/p51 dimerization (By similarity).

Integrase

The core domain contains the D-x(n)-D-x35-E motif, named for the phylogenetically conserved glutamic acid and aspartic acid residues and the invariant 35 amino acid spacing between the second and third acidic residues. Each acidic residue of the D,D35E motif is independently essential for the 3'-processing and strand transfer activities of purified integrase protein.

Keywords

Family and domain databases

Sequence & Isoform

Align isoforms (2)
  • Sequence status
    Complete

This entry describes 2 isoforms produced by Ribosomal frameshifting. Translation results in the formation of the Gag polyprotein most of the time. Ribosomal frameshifting at the gag-pol genes boundary occurs at low frequency and produces the Gag-Pol polyprotein. This strategy of translation probably allows the virus to modulate the quantity of each viral protein. Maintenance of a correct Gag to Gag-Pol ratio is essential for RNA dimerization and viral infectivity.

P04588-1

This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

  • Name
    Gag-Pol polyprotein
  • Note
    Produced by -1 ribosomal frameshifting.
  • See also
    sequence in UniParc or sequence clusters in UniRef
  • Length
    1,440
  • Mass (Da)
    162,122
  • Last updated
    2007-01-23 v3
  • Checksum
    D212FABD311A9AB8
MGARASVLSGGKLDAWEKIRLRPGGKKKYRLKHLVWASRELERFALNPGLLETGEGCQQIMEQLQSTLKTGSEEIKSLYNTVATLYCVHQRIDVKDTKEALDKIEEIQNKSRQKTQQAAAAQQAAAATKNSSSVSQNYPIVQNAQGQMIHQAISPRTLNAWVKVIEEKAFSPEVIPMFSALSEGATPQDLNMMLNIVGGHQAAMQMLKDTINEEAADWDRVHPVHAGPIPPGQMREPRGSDIAGTTSTLQEQIGWMTSNPPIPVGDIYKRWIILGLNKIVRMYSPVSILDIRQGPKEPFRDYVDRFFKTLRAEQATQEVKNWMTETLLVQNANPDCKTILKALGPGATLEEMMTACQGVGGPSHKARVLAEAMSQATNSTAAIMMQRGNFKGQKRIKCFNCGKEGHLARNCRAPRKKGCWKCGKEGHQMKDCTERQANFLRENLAFPQGKAREFPSEQTRANSPTSRELRVWGGDKTLSETGAERQGIVSFSFPQITLWQRPVVTVRVGGQLKEALLDTGADDTVLEEINLPGKWKPKMIGGIGGFIKVRQYDQILIEICGKKAIGTILVGPTPVNIIGRNMLTQIGCTLNFPISPIETVPVKLKPGMDGPRVKQWPLTEEKIKALTEICKDMEKEGKILKIGPENPYNTPVFAIKKKDSTKWRKLVNFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSVPLDEDFRKYTAFTIPSINNETPGIRYQYNVLPQGWKGSPAIFQSSMTKILEPFRTKNPEIVIYQYMDDLYVGSDLEIGQHRTKIEELREHLLKWGFTTPDKKHQKEPPFLWMGYELHPDKWTVQPIQLPDKESWTVNDIQKLVGKLNWASQIYPGIKVKQLCKLLRGAKALTDIVPLTAEAELELAENREILKEPVHGVYYDPSKDLIAEIQKQGQGQWTYQIYQEQYKNLKTGKYARIKSAHTNDVKQLTEAVQKIAQESIVIWGKTPKFRLPIQKETWEAWWTEYWQATWIPEWEFVNTPPLVKLWYQLETEPIVGAETFYVDGAANRETKKGKAGYVTDRGRQKVVSLTETTNQKTELQAIHLALQDSGSEVNIVTDSQYALGIIQAQPDKSESEIVNQIIEQLIQKDKVYLSWVPAHKGIGGNEQVDKLVSSGIRKVLFLDGIDKAQEEHEKYHSNWRAMASDFNLPPIVAKEIVASCDKCQLKGEAMHGQVDCSPGIWQLDCTHLEGKIIIVAVHVASGYIEAEVIPAETGQETAYFILKLAGRWPVKVVHTDNGSNFTSAAVKAACWWANIKQEFGIPYNPQSQGVVESMNKELKKIIGQVREQAEHLKTAVQMAVFIHNFKRKGGIGGYSAGERIIDMIATDIQTKELQKQITKIQNFRVYYRDNRDPIWKGPAKLLWKGEGAVVIQDNSDIKVVPRRKAKIIRDYGKQMAGDDCVAGGQDED

P04594-1

The sequence of this isoform can be found in the external entry linked below. Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.

View isoform
  • Name
    Gag polyprotein
  • See also
    sequence in UniParc or sequence clusters in UniRef

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
X04415
EMBL· GenBank· DDBJ
CAA28012.1
EMBL· GenBank· DDBJ
Genomic RNA Sequence problems.

Similar Proteins

Disclaimer

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