Sandbox Reserved 958

From Proteopedia

Dimer of HIV-1 integrase catalytic core domain is the active form of the 3'-Processing reaction that occurs in patients cells suffering from AIDS. The catalytic core domain is just one of three parts composing the HIV-1 integrase. This enzyme performs mainly two specific reactions : the 3'-processing and the integration of the viral DNA into the host genome. In vivo we can find this protein in several forms such as monomer, dimers and tetramers^[1].

Biological role

Acquired Immune Defficiency Syndrome (AIDS) is a human disease caused by the Human Imunnodeficiency Virus (HIV) which is part of the retroviral virus family. This virus infects immune system's cells (Lymphocytes, Macrophages or Dendritic Cells,...) and provoke their destruction by highjacking the cellular machinery.

In the first step the virus penetrates the cell through specific membrane receptors then the Retrotranscriptase transforms the viral RNA into a double strand DNA. Further, it will be integrated into the cellular DNA by association with the integrase and other viral and cellular proteins to form the Pre-Integration Complex (PIC). In the last step several viral proteins will be expressed and new virions will be formed by packaging viral and cellular proteins but also the viral RNA ^[2].

This process leads to an Imunnodeficiency that can indirectly undergo death by an opportunic infection.

Structure

The HIV-1 integrase is a 288-amino acids length of 32 kDa expressed by the Pol gene. It leads to the synthesis of a polyprotein named Gag-Pol which will be cleaved by the HIV-protease and produced several proteins including integrase. This structure consists of two catalytic core domain monomers. Each monomer is composed of surrounded by . This protein is divided in three main domains: the N-terminal, the central and the C-terminal domain.

The N-terminal domain presents a HHCC motif which is a pseudo zinc-finger complexing with zinc ions. The zinc ejection impedes the 3'-processing process and pertubs the integrase multimerisation^[3]. Therefore the presence of this ion is necessary the virus life cycle.

The central domain which corresponds to the catalytic domain contains the by association of two aspartates and one glutamate residues that coordinate bivalent ions, Cd++ in this structure but Mg++ or Mn++ in vivo ^[4]. This domain contains between the 170-180 position involved in the packaging of the Uracil DNA glycosylase (UNG2)^[5] essential for the viral replication.

The C-terminale domain allows the DNA binding in a non-specific manner and it is also involved in the stability of the complex with DNA^[6].

DNA binding

Function

Integrase is the most conserved protein of the HIV, it means that this enzyme is essential for its life cycle. It has many functions during a cell infection :

- in vivo it catalyzes the transport the viral DNA into the nucleus, it interacts with many proteins (VPR, VBP1, HIV-matrix,...) and DNA to form the Pre-Integration Complex (PIC) and allow the integration of the viral DNA into host genome and this mechanism can be divided in two reactions, the 3'-Processing and the Strand Transfer^[1]

- in vitro researchers proved that two more reactions can be catalyzed by the integrase, the disintegration of the viral DNA and also a possible DNA polymerase activity^[4] to repair mismatches during integration.

3'-Processing

The 3'-processing is a reaction where the integrase and most precisely, the N-ter domain catalyzes the excision of two 3'-terminal nucleotides due to a nucleophilic attack using water. Dimers of IN are formed to induce this reaction, then these two dimers are linked on the viral DNA extremities to form a tetramer of IN.

Strand Transfer

Posttranslationnal Modifications

Inhibitors

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.

</StructureSection>

References

1. ↑ ^{1.0 1.1} Delelis O, Carayon K, Saib A, Deprez E, Mouscadet JF. Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology. 2008 Dec 17;5:114. doi: 10.1186/1742-4690-5-114. PMID:19091057 doi:http://dx.doi.org/10.1186/1742-4690-5-114
2. ↑ Barre-Sinoussi F, Ross AL, Delfraissy JF. Past, present and future: 30 years of HIV research. Nat Rev Microbiol. 2013 Dec;11(12):877-83. doi: 10.1038/nrmicro3132. Epub 2013, Oct 28. PMID:24162027 doi:http://dx.doi.org/10.1038/nrmicro3132
3. ↑ Carayon K, Leh H, Henry E, Simon F, Mouscadet JF, Deprez E. A cooperative and specific DNA-binding mode of HIV-1 integrase depends on the nature of the metallic cofactor and involves the zinc-containing N-terminal domain. Nucleic Acids Res. 2010 Jun;38(11):3692-708. doi: 10.1093/nar/gkq087. Epub 2010, Feb 17. PMID:20164093 doi:http://dx.doi.org/10.1093/nar/gkq087
4. ↑ ^{4.0 4.1} Liao C, Marchand C, Burke TR Jr, Pommier Y, Nicklaus MC. Authentic HIV-1 integrase inhibitors. Future Med Chem. 2010 Jul;2(7):1107-22. doi: 10.4155/fmc.10.199. PMID:21426159 doi:http://dx.doi.org/10.4155/fmc.10.199
5. ↑ Zheng Y, Yao X. Posttranslational modifications of HIV-1 integrase by various cellular proteins during viral replication. Viruses. 2013 Jul 16;5(7):1787-801. doi: 10.3390/v5071787. PMID:23863879 doi:http://dx.doi.org/10.3390/v5071787
6. ↑ Tsuruyama T, Nakai T, Ohmori R, Ozeki M, Tamaki K, Yoshikawa K. Dialysis purification of integrase-DNA complexes provides high-resolution atomic force microscopy images: dimeric recombinant HIV-1 integrase binding and specific looping on DNA. PLoS One. 2013;8(1):e53572. doi: 10.1371/journal.pone.0053572. Epub 2013 Jan 14. PMID:23341952 doi:http://dx.doi.org/10.1371/journal.pone.0053572