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Cyclophilin A interacts with diverse lentiviral capsids.

Lin TY, Emerman M - Retrovirology (2006)

Bottom Line: This binding positively affects some early stage of the viral life-cycle because prevention of binding either by drugs that occupy that active site of cyclophilin A, by mutation in HIV-1 CA, or RNAi that knocks down intracellular CypA level diminishes viral infectivity.We find that diverse lentiviruses, FIV and SIVagmTAN also bind to CypA.Mutagenesis of FIV CA showed that an amino acid that is in a homologous position to the proline at amino acid 90 of HIV-1 CA is essential for FIV interactions with CypA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pathobiology Graduate Program, University of Washington, Seattle, WA 98195, USA. linty@u.washington.edu

ABSTRACT

Background: The capsid (CA) protein of HIV-1 binds with high affinity to the host protein cyclophilin A (CypA). This binding positively affects some early stage of the viral life-cycle because prevention of binding either by drugs that occupy that active site of cyclophilin A, by mutation in HIV-1 CA, or RNAi that knocks down intracellular CypA level diminishes viral infectivity. The closely related lentivirus, SIVcpz also binds CypA, but it was thought that this interaction was limited to the HIV-1/SIVcpz lineage because other retroviruses failed to interact with CypA in a yeast two-hybrid assay.

Results: We find that diverse lentiviruses, FIV and SIVagmTAN also bind to CypA. Mutagenesis of FIV CA showed that an amino acid that is in a homologous position to the proline at amino acid 90 of HIV-1 CA is essential for FIV interactions with CypA.

Conclusion: These results demonstrate that CypA binding to lentiviruses is more widespread than previously thought and suggest that this interaction is evolutionarily important for lentiviral infection.

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Computer modelling of the CA structure from SIVmac and SIVagmTAN. The CA structure from SIVmac and SIVagmTAN by using HIV-1 CA crystal structure (PDB:1AK4) as template. The CA from SIVmac (upper panel) and SIVagmTAN (lower panel) were superimposed on the CA from HIV-1 which binds to CypA. The proline at position 90 on HIV-1 CA is indicated.
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Figure 6: Computer modelling of the CA structure from SIVmac and SIVagmTAN. The CA structure from SIVmac and SIVagmTAN by using HIV-1 CA crystal structure (PDB:1AK4) as template. The CA from SIVmac (upper panel) and SIVagmTAN (lower panel) were superimposed on the CA from HIV-1 which binds to CypA. The proline at position 90 on HIV-1 CA is indicated.

Mentions: We determined that the proline at amino acid 90 on FIV CA is critical for the interaction with CypA. This is similar to the site on HIV-1 that binds CypA, suggesting the proline in the middle of the loop is crucial for CypA recognition. However, the CA sequence alignment of SIVmac with HIV-1 shows that SIVmac also possesses this corresponding proline (Fig. 5A). The major difference of the loop between the fourth and fifth alpha-helices in HIV-1 and SIVmac is its length. We applied the SWISS-MODEL computer modelling to generate putative structure of CA from SIVmac and SIVagmTAN based on the crystal structure of HIV-1 CA bound to CypA (PDB:1AK4). We found that the CypA-binding loop of SIVagmTAN can be superimposed on the parallel loop of HIV-1 well, while the loop of SIVmac is shorter than that of HIV-1 and is not able to fit in the HIV-1 scale (Fig. 6). This suggests that in addition to the proline at position 90 (based on HIV-1), the length of the loop also contributes to the CypA binding. A shorter loop might not be able to insert into the binding groove of CypA even though the target proline is present in the middle of the loop. On the other hand, Cyclophilin B (CypB), another member in the cyclophilin family, was showed to interact with Gag proteins from HIV-1 and SIVmac [1,2]. However, the CypB/Gag interaction in both HIV-1 and SIVmac is not mediated by binding of CypB to the same loop that CypA recognizes. To our knowledge, the CypB/Gag interaction has not been reported to affect viral replication.


Cyclophilin A interacts with diverse lentiviral capsids.

Lin TY, Emerman M - Retrovirology (2006)

Computer modelling of the CA structure from SIVmac and SIVagmTAN. The CA structure from SIVmac and SIVagmTAN by using HIV-1 CA crystal structure (PDB:1AK4) as template. The CA from SIVmac (upper panel) and SIVagmTAN (lower panel) were superimposed on the CA from HIV-1 which binds to CypA. The proline at position 90 on HIV-1 CA is indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1622752&req=5

Figure 6: Computer modelling of the CA structure from SIVmac and SIVagmTAN. The CA structure from SIVmac and SIVagmTAN by using HIV-1 CA crystal structure (PDB:1AK4) as template. The CA from SIVmac (upper panel) and SIVagmTAN (lower panel) were superimposed on the CA from HIV-1 which binds to CypA. The proline at position 90 on HIV-1 CA is indicated.
Mentions: We determined that the proline at amino acid 90 on FIV CA is critical for the interaction with CypA. This is similar to the site on HIV-1 that binds CypA, suggesting the proline in the middle of the loop is crucial for CypA recognition. However, the CA sequence alignment of SIVmac with HIV-1 shows that SIVmac also possesses this corresponding proline (Fig. 5A). The major difference of the loop between the fourth and fifth alpha-helices in HIV-1 and SIVmac is its length. We applied the SWISS-MODEL computer modelling to generate putative structure of CA from SIVmac and SIVagmTAN based on the crystal structure of HIV-1 CA bound to CypA (PDB:1AK4). We found that the CypA-binding loop of SIVagmTAN can be superimposed on the parallel loop of HIV-1 well, while the loop of SIVmac is shorter than that of HIV-1 and is not able to fit in the HIV-1 scale (Fig. 6). This suggests that in addition to the proline at position 90 (based on HIV-1), the length of the loop also contributes to the CypA binding. A shorter loop might not be able to insert into the binding groove of CypA even though the target proline is present in the middle of the loop. On the other hand, Cyclophilin B (CypB), another member in the cyclophilin family, was showed to interact with Gag proteins from HIV-1 and SIVmac [1,2]. However, the CypB/Gag interaction in both HIV-1 and SIVmac is not mediated by binding of CypB to the same loop that CypA recognizes. To our knowledge, the CypB/Gag interaction has not been reported to affect viral replication.

Bottom Line: This binding positively affects some early stage of the viral life-cycle because prevention of binding either by drugs that occupy that active site of cyclophilin A, by mutation in HIV-1 CA, or RNAi that knocks down intracellular CypA level diminishes viral infectivity.We find that diverse lentiviruses, FIV and SIVagmTAN also bind to CypA.Mutagenesis of FIV CA showed that an amino acid that is in a homologous position to the proline at amino acid 90 of HIV-1 CA is essential for FIV interactions with CypA.

View Article: PubMed Central - HTML - PubMed

Affiliation: Pathobiology Graduate Program, University of Washington, Seattle, WA 98195, USA. linty@u.washington.edu

ABSTRACT

Background: The capsid (CA) protein of HIV-1 binds with high affinity to the host protein cyclophilin A (CypA). This binding positively affects some early stage of the viral life-cycle because prevention of binding either by drugs that occupy that active site of cyclophilin A, by mutation in HIV-1 CA, or RNAi that knocks down intracellular CypA level diminishes viral infectivity. The closely related lentivirus, SIVcpz also binds CypA, but it was thought that this interaction was limited to the HIV-1/SIVcpz lineage because other retroviruses failed to interact with CypA in a yeast two-hybrid assay.

Results: We find that diverse lentiviruses, FIV and SIVagmTAN also bind to CypA. Mutagenesis of FIV CA showed that an amino acid that is in a homologous position to the proline at amino acid 90 of HIV-1 CA is essential for FIV interactions with CypA.

Conclusion: These results demonstrate that CypA binding to lentiviruses is more widespread than previously thought and suggest that this interaction is evolutionarily important for lentiviral infection.

Show MeSH
Related in: MedlinePlus