Q1A249 · POL_SIVEK

Function

function

Gag-Pol polyprotein and Gag polyprotein may regulate their own translation, by the binding genomic RNA in the 5'-UTR. At low concentration, Gag-Pol and Gag would promote translation, whereas at high concentration, the polyproteins encapsidate genomic RNA and then shut off translation (By similarity).
Matrix protein p17 has two main functions: in infected cell, it targets Gag and Gag-pol polyproteins to the plasma membrane via a multipartite membrane-binding signal, that includes its myristointegration complex. The myristoylation signal and the NLS exert conflicting influences its subcellular localization. The key regulation of these motifs might be phosphorylation of a portion of MA molecules on the C-terminal tyrosine at the time of virus maturation, by virion-associated cellular tyrosine kinase. Implicated in the release from host cell mediated by Vpu (By similarity).
Capsid protein p24 forms the conical core that encapsulates the genomic RNA-nucleocapsid complex in the virion. The core is constituted by capsid protein hexamer subunits. The core is disassembled soon after virion entry. Interaction with host PPIA/CYPA protects the virus from restriction by host TRIM5-alpha and from an unknown antiviral activity in host cells. This capsid restriction by TRIM5 is one of the factors which restricts SIV to the simian species (By similarity).
Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. Facilitates rearangement of nucleic acid secondary structure during retrotranscription of genomic RNA. This capability is referred to as nucleic acid chaperone activity (By similarity).
The aspartyl protease 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 (By similarity).
Reverse transcriptase/ribonuclease H (RT) is a multifunctional enzyme that converts the viral dimeric 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 tRNA 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 can probably 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 (By similarity).
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 SIV genome, a 5 bp duplication of host DNA is produced at the ends of SIV integration. Alternatively, Integrase may catalyze the excision of viral DNA just after strand transfer, this is termed disintegration (By similarity).

Miscellaneous

The reverse transcriptase is an 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.

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

The viral protease is inhibited by many synthetic protease inhibitors (PIs), such as amprenavir, atazanavir, indinavir, loprinavir, nelfinavir, ritonavir and saquinavir. 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. Use of protease inhibitors in tritherapy regimens permit more ambitious therapeutic strategies.

Features

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

TypeIDPosition(s)Description
Site135-136Cleavage; by viral protease
Site224-225Cis/trans isomerization of proline peptide bond; by human PPIA/CYPA
Site366-367Cleavage; by viral protease
Site380-381Cleavage; by viral protease
Site435-436Cleavage; by viral protease
Site497-498Cleavage; by viral protease
Active site522For protease activity; shared with dimeric partner
Site596-597Cleavage; by viral protease
Binding site706Mg2+ 1 (UniProtKB | ChEBI); catalytic; for reverse transcriptase activity
Binding site781Mg2+ 1 (UniProtKB | ChEBI); catalytic; for reverse transcriptase activity
Binding site782Mg2+ 1 (UniProtKB | ChEBI); catalytic; for reverse transcriptase activity
Site997Essential for RT p66/p51 heterodimerization
Site1010Essential for RT p66/p51 heterodimerization
Site1036-1037Cleavage; by viral protease
Binding site1039Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Binding site1074Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Binding site1094Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Binding site1145Mg2+ 2 (UniProtKB | ChEBI); catalytic; for RNase H activity
Site1156-1157Cleavage; by viral protease
Binding site1168Zn2+ (UniProtKB | ChEBI)
Binding site1172Zn2+ (UniProtKB | ChEBI)
Binding site1196Zn2+ (UniProtKB | ChEBI)
Binding site1199Zn2+ (UniProtKB | ChEBI)
Binding site1220Mg2+ 3 (UniProtKB | ChEBI); catalytic; for integrase activity
Binding site1272Mg2+ 3 (UniProtKB | ChEBI); catalytic; for integrase activity
DNA binding1379-1426Integrase-type

GO annotations

AspectTerm
Cellular Componenthost cell
Cellular Componenthost cell cytoplasm
Cellular Componenthost cell nucleus
Cellular Componenthost cell plasma membrane
Cellular Componentmembrane
Cellular Componentviral nucleocapsid
Molecular Functionaspartic-type endopeptidase activity
Molecular FunctionDNA binding
Molecular FunctionDNA-directed DNA polymerase activity
Molecular Functionexoribonuclease H activity
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 suppression of host gene expression
Biological Processviral genome integration into host DNA
Biological Processviral penetration into host nucleus
Biological Processviral translational frameshifting

Keywords

Names & Taxonomy

Protein names

Gene names

    • Name
      gag-pol

Organism names

Accessions

  • Primary accession
    Q1A249

Proteomes

Subcellular Location

Matrix protein p17

Virion
Host nucleus
Host cytoplasm
Host cell membrane
; Lipid-anchor
Note: Following virus entry, the nuclear localization signal (NLS) of the matrix protein participates with Vpr to the nuclear localization of the viral genome. During virus production, the nuclear export activity of the matrix protein counteracts the NLS to maintain the Gag and Gag-Pol polyproteins in the cytoplasm, thereby directing unspliced RNA to the plasma membrane (By similarity).

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

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_00002493742-135Matrix protein p17
ChainPRO_00002613022-1448Gag-Pol polyprotein
Modified residue135Phosphotyrosine; by host
ChainPRO_0000249375136-366Capsid protein p24
PeptidePRO_0000249376367-380Spacer peptide p2
ChainPRO_0000249377381-435Nucleocapsid protein p7
ChainPRO_0000249379436-497p6-pol
ChainPRO_0000249380498-596Protease
ChainPRO_0000249382597-1036p51 RT
ChainPRO_0000249381597-1156Reverse transcriptase/ribonuclease H
ChainPRO_00002493831037-1156p15
ChainPRO_00002493841157-1448Integrase

Post-translational modification

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.
Capsid protein p24 is phosphorylated.

Keywords

Interaction

Subunit

Matrix protein p17

Homotrimer. Interacts with gp41 (via C-terminus).

Protease

Homodimer. The active site consists of two apposed aspartic acid residues.

Reverse transcriptase/ribonuclease H

Heterodimer of p66 RT and p51 RT (RT p66/p51). Heterodimerization of RT is essential for DNA polymerase activity. Despite the sequence identities, p66 RT and p51 RT have distinct folding.

Integrase

Homotetramer; may further associate as a homohexadecamer (By similarity).

Structure

3D structure databases

Family & Domains

Features

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

TypeIDPosition(s)Description
Motif16-22Nuclear export signal
Motif26-32Nuclear localization signal
Region107-129Disordered
Zinc finger393-410CCHC-type 1
Zinc finger414-431CCHC-type 2
Region446-490Disordered
Compositional bias472-490Basic and acidic residues
Domain517-586Peptidase A2
Domain640-830Reverse transcriptase
Region823-831RT 'primer grip'
Motif994-1010Tryptophan repeat motif
Domain1030-1153RNase H type-1
Zinc finger1159-1200Integrase-type
Domain1210-1360Integrase catalytic

Domain

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

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.

Q1A249-1

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
    1,448
  • Mass (Da)
    163,246
  • Last updated
    2007-01-23 v3
  • Checksum
    0147967C358DBB01
MGARASVLTGGKLDQWEKIYLRPGGKKKYMMKHLVWASRELERFACNPGLMDTAEGCAQLLRQLEPALKTGSEGLRSLFNTLAVLYCVHNNIKVQNTQEALEKLREKMKAEQKEPEPEQAAGAAAAPESSISRNYPLVQNAQGQMVHQPLSPRTLNAWVKVVEEKAFNPEVIPMFMALSEGATPQDLNTMLNTVGGHQAAMQMLKEVINEEAAEWDRGHPVHMGPIPPGQVREPRGSDIAGTTSTLAEQVAWMTANPPVPVGDIYRRWIVLGLNKIVRMYSPASILDIKQGPKETFRDYVDRFYKTLRAEQATQEVKNWMTETLLVQNANPDCKNILRALGPGASLEEMMTACQGVGGPAHKARVLAEAMTQAQTATSVFMQRGNFKGIRKTIKCFNCGKEGHLARNCKAPRKKGCWKCGQEGHQMKDCRSGERQFFREGLASLQREARKFPPDNNKERANSPSNRELWVSGGEDHTGDREGRKGEDRELSVPTLNFPQITLWQRPILTVKIGGEIKEALLDTGADDTVIEEIQLEGKWKPKMIGGIGGFIKVKQYDNVIIEIQGKKAVGTVLVGPTPVNIIGRNFLTQIGCTLNFPISPIETIPVKLKPGMDGPRVKQWPLTEEKIKALTEICTEMEKEGKISRIGPENPYNTPIFAIKKKDSTKWRKLVDFRELNKRTQDFWEVQLGIPHPAGLKKKKSVTVLDVGDAYFSCPLDENFRKYTAFTIPSVNNETPGIRYQYNVLPQGWKGSPAIFQSTMTKILEPFRKNNPELVIYQYMDDLYVGSDLEITQHREAVERLRSHLLTWGFTTPDKKHQKEPPFLWMGYELHPDKWTVQTIQLPEKDTWTVNDIQQLVGKLNWASQIYPGIKVKQLCKLIRGAKALTEVVTLTREAELELAENREILKEPVHGAYYNPDKELIAEIQKQGQGQWTYQIYQDLHKNLKTGKYAKMRSTHTNDIRQLTEVVQKVALESIVIWGKTPKFRLPVQKEVWETWWTEYWQATWIPDWEFVNTPPLVKLWYQLETEPISGAETYYVDGAANRETKLGKAGFVTDRGRQKVTSISETTNQQAELQAVLMALQDAGQEVNIVTDSQYVLGIIHSQPDKSESELVNQIIEELIKKERIYLSWVPAHKGIGGNEQIDKLVSTGIRKVLFLDGIDKAQEEHERYHSNWKAMASDFNLPPIVAKEIVASCDKCQLKGEAIHGQINCSPGVWQLDCTHLEGKIILVAVHVASGYLEAEVIPAETGQETAYFILKLAGRWPVKVIHTDNGSNFTSATVKAACWWANIQQEFGIPYNPQSQGAVESMNKELKKIIGQIRDQAEHLKTAVQMAVFIHNFKRKGGIGGYTAGERIIDIIATDIQTTKLQTQILKVQNFRVYYRDSREPTWKGPAKLLWKGEGAVVIQDNGDIKVVPRRKAKIIRDYGKQMAGDGCVASGQDESQDME

Q1A250-1

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

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias472-490Basic and acidic residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
DQ373065
EMBL· GenBank· DDBJ
ABD19493.1
EMBL· GenBank· DDBJ
Genomic RNA Sequence problems.

Similar Proteins

Disclaimer

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