P05896 (POL_SIVM1) Reviewed, UniProtKB/Swiss-Prot
Last modified February 19, 2014. Version 132. History...
Names and origin
|Protein names||Recommended name:|
Cleaved into the following 9 chains:
|Organism||Simian immunodeficiency virus (isolate Mm142-83) (SIV-mac) (Simian immunodeficiency virus rhesus monkey) [Complete proteome]|
|Taxonomic identifier||11733 [NCBI]|
|Taxonomic lineage||Viruses › Retro-transcribing viruses › Retroviridae › Orthoretrovirinae › Lentivirus › Primate lentivirus group ›|
|Virus host||Cercopithecidae (Old World monkeys) [TaxID: 9527]|
|Sequence length||1448 AA.|
|Sequence processing||The displayed sequence is further processed into a mature form.|
|Protein existence||Evidence at protein level|
General annotation (Comments)
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 shutt 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.
Specific for a P1 residue that is hydrophobic, and P1' variable, but often Pro.
Endohydrolysis of RNA in RNA/DNA hybrids. Three different cleavage modes: 1. sequence-specific internal cleavage of RNA. Human immunodeficiency virus type 1 and Moloney murine leukemia virus enzymes prefer to cleave the RNA strand one nucleotide away from the RNA-DNA junction. 2. RNA 5'-end directed cleavage 13-19 nucleotides from the RNA end. 3. DNA 3'-end directed cleavage 15-20 nucleotides away from the primer terminus.
3'-end directed exonucleolytic cleavage of viral RNA-DNA hybrid.
Deoxynucleoside triphosphate + DNA(n) = diphosphate + DNA(n+1).
Binds 2 magnesium ions for reverse transcriptase polymerase activity By similarity.
Binds 2 magnesium ions for ribonuclease H (RNase H) activity. Substrate-binding is a precondition for magnesium binding By similarity.
Magnesium ions for integrase activity. Binds at least 1, maybe 2 magnesium ions By similarity.
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.
Matrix protein p17 is a trimer. Interacts with gp120. The protease is a homodimer, whose active site consists of two apposed aspartic acid residues. The reverse transcriptase is a 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. The integrase is a homodimer and possibly a homotetramer By similarity.
Matrix protein p17: Virion Potential. Host nucleus By similarity. Host cytoplasm By similarity. Host cell membrane; Lipid-anchor Potential. 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.
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 By similarity.
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 By similarity.
Capsid protein p24 is phosphorylated.
This is a macaque isolate.
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.
Contains 2 CCHC-type zinc fingers.
Contains 1 integrase catalytic domain.
Contains 1 integrase-type DNA-binding domain.
Contains 1 integrase-type zinc finger.
Contains 1 peptidase A2 domain.
Contains 1 reverse transcriptase domain.
Contains 1 RNase H domain.
|This entry describes 2 isoforms produced by ribosomal frameshifting. [Align] [Select]|
Note: 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.
|Isoform Gag-Pol polyprotein (identifier: P05896-1) |
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.
|Note: Produced by -1 ribosomal frameshifting.|
|Isoform Gag polyprotein (identifier: P05894-1) |
The sequence of this isoform can be found in the external entry P05894.
Isoforms of the same protein are often annotated in two different entries if their sequences differ significantly.
|Note: Produced by conventional translation.|
Sequence annotation (Features)
|Feature key||Position(s)||Length||Description||Graphical view||Feature identifier|
|Initiator methionine||1||1||Removed; by host By similarity|
|Chain||2 – 1448||1447||Gag-Pol polyprotein||PRO_0000306035|
|Chain||2 – 135||134||Matrix protein p17 By similarity||PRO_0000306036|
|Chain||136 – 364||229||Capsid protein p24 By similarity||PRO_0000306037|
|Chain||365 – 433||69||Nucleocapsid protein p7 By similarity||PRO_0000306038|
|Chain||434 – 500||67||p6-pol Potential||PRO_0000306039|
|Chain||501 – 596||96||Protease By similarity||PRO_0000306040|
|Chain||597 – 1155||559||Reverse transcriptase/ribonuclease H By similarity||PRO_0000306041|
|Chain||597 – 1035||439||p51 RT By similarity||PRO_0000306042|
|Chain||1036 – 1155||120||p15 By similarity||PRO_0000306043|
|Chain||1156 – 1448||293||Integrase By similarity||PRO_0000306044|
|Domain||517 – 586||70||Peptidase A2|
|Domain||640 – 830||191||Reverse transcriptase|
|Domain||1029 – 1152||124||RNase H|
|Domain||1209 – 1359||151||Integrase catalytic|
|Zinc finger||391 – 408||18||CCHC-type 1|
|Zinc finger||412 – 429||18||CCHC-type 2|
|Zinc finger||1158 – 1199||42||Integrase-type|
|DNA binding||1378 – 1425||48||Integrase-type|
|Region||823 – 831||9||RT 'primer grip' By similarity|
|Motif||16 – 22||7||Nuclear export signal By similarity|
|Motif||26 – 32||7||Nuclear localization signal By similarity|
|Motif||993 – 1009||17||Tryptophan repeat motif By similarity|
|Active site||522||1||For protease activity; shared with dimeric partner By similarity|
|Metal binding||706||1||Magnesium; catalytic; for reverse transcriptase activity By similarity|
|Metal binding||781||1||Magnesium; catalytic; for reverse transcriptase activity By similarity|
|Metal binding||782||1||Magnesium; catalytic; for reverse transcriptase activity By similarity|
|Metal binding||1038||1||Magnesium; catalytic; for RNase H activity By similarity|
|Metal binding||1073||1||Magnesium; catalytic; for RNase H activity By similarity|
|Metal binding||1093||1||Magnesium; catalytic; for RNase H activity By similarity|
|Metal binding||1144||1||Magnesium; catalytic; for RNase H activity By similarity|
|Metal binding||1219||1||Magnesium; catalytic; for integrase activity By similarity|
|Metal binding||1271||1||Magnesium; catalytic; for integrase activity By similarity|
|Site||135 – 136||2||Cleavage; by viral protease By similarity|
|Site||364 – 365||2||Cleavage; by viral protease By similarity|
|Site||433 – 434||2||Cleavage; by viral protease By similarity|
|Site||500 – 501||2||Cleavage; by viral protease By similarity|
|Site||596 – 597||2||Cleavage; by viral protease By similarity|
|Site||996||1||Essential for RT p66/p51 heterodimerization By similarity|
|Site||1009||1||Essential for RT p66/p51 heterodimerization By similarity|
|Site||1035 – 1036||2||Cleavage; by viral protease By similarity|
|Site||1155 – 1156||2||Cleavage; by viral protease By similarity|
Amino acid modifications
|Lipidation||2||1||N-myristoyl glycine; by host By similarity|
Helix Strand Turn
|Beta strand||502 – 504||3|
|Beta strand||507 – 512||6|
|Beta strand||515 – 521||7|
|Beta strand||525 – 527||3|
|Beta strand||540 – 544||5|
|Beta strand||551 – 563||13|
|Beta strand||566 – 575||10|
|Helix||584 – 589||6|
|Beta strand||593 – 595||3|
|Beta strand||1215 – 1223||9|
|Beta strand||1226 – 1232||7|
|Beta strand||1239 – 1243||5|
|Helix||1249 – 1260||12|
|Beta strand||1267 – 1269||3|
|Helix||1280 – 1288||9|
|Beta strand||1291 – 1293||3|
|Turn||1309 – 1311||3|
|Helix||1312 – 1318||7|
|Turn||1319 – 1322||4|
|Beta strand||1323 – 1325||3|
|Helix||1327 – 1339||13|
|Beta strand||1344 – 1347||4|
|Helix||1351 – 1363||13|
|||"Sequence of simian immunodeficiency virus from macaque and its relationship to other human and simian retroviruses."|
Chakrabarti L., Guyader M., Alizon M., Daniel M.D., Desrosiers R.C., Tiollais P., Sonigo P.
Nature 328:543-547(1987) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
|||"Domain flexibility in retroviral proteases: structural implications for drug resistant mutations."|
Rose R.B., Craik C.S., Stroud R.M.
Biochemistry 37:2607-2621(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 498-595.
|+||Additional computationally mapped references.|
|Y00277 Genomic DNA. Translation: CAA68380.1.|
3D structure databases
|SMR||P05896. Positions 2-135, 146-352, 383-432, 498-596, 599-1151, 1156-1201, 1210-1368, 1371-1425. |
Protocols and materials databases
Family and domain databases
|Gene3D||220.127.116.11. 1 hit. |
1.10.1200.30. 1 hit.
18.104.22.168. 1 hit.
1.10.375.10. 1 hit.
22.214.171.124. 1 hit.
126.96.36.199. 1 hit.
188.8.131.52. 1 hit.
|InterPro||IPR001969. Aspartic_peptidase_AS. |
|Pfam||PF00540. Gag_p17. 1 hit. |
PF00607. Gag_p24. 1 hit.
PF00552. IN_DBD_C. 1 hit.
PF02022. Integrase_Zn. 1 hit.
PF00075. RNase_H. 1 hit.
PF00665. rve. 1 hit.
PF00077. RVP. 1 hit.
PF00078. RVT_1. 1 hit.
PF06815. RVT_connect. 1 hit.
PF06817. RVT_thumb. 1 hit.
PF00098. zf-CCHC. 2 hits.
|PRINTS||PR00234. HIV1MATRIX. |
|SMART||SM00343. ZnF_C2HC. 2 hits. |
|SUPFAM||SSF46919. SSF46919. 1 hit. |
SSF47353. SSF47353. 1 hit.
SSF47836. SSF47836. 1 hit.
SSF47943. SSF47943. 1 hit.
SSF50122. SSF50122. 1 hit.
SSF50630. SSF50630. 1 hit.
SSF53098. SSF53098. 2 hits.
SSF57756. SSF57756. 1 hit.
|PROSITE||PS50175. ASP_PROT_RETROV. 1 hit. |
PS00141. ASP_PROTEASE. 1 hit.
PS50994. INTEGRASE. 1 hit.
PS51027. INTEGRASE_DBD. 1 hit.
PS50879. RNASE_H. 1 hit.
PS50878. RT_POL. 1 hit.
PS50158. ZF_CCHC. 2 hits.
PS50876. ZF_INTEGRASE. 1 hit.
|Accession||Primary (citable) accession number: P05896|
|Entry status||Reviewed (UniProtKB/Swiss-Prot)|
|Annotation program||Viral Protein Annotation Program|