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Viroporin potential of the lentivirus lytic peptide (LLP) domains of the HIV-1 gp41 protein.

Costin JM, Rausch JM, Garry RF, Wimley WC - Virol. J. (2007)

Bottom Line: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development.These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin.Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biotechnology Research Group, Department of Biology, Florida Gulf Coast University, 10501 FGCU Blvd. S., Fort Myers, FL 33965, USA. jcostin@fgcu.edu

ABSTRACT

Background: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development. Virally induced changes in membrane ionic permeability induced by lytic viruses of many families contribute to cytopathogenesis. HIV-1 induces disturbances in plasma membrane ion transport. The carboxyl terminus of TM (gp41) contains potential amphipathic alpha-helical motifs identified through their structural similarities to naturally occurring cytolytic peptides. These sequences have been dubbed lentiviral lytic peptides (LLP) -1, -2, and -3.

Results: Peptides corresponding to the LLP domains (from a clade B virus) partition into lipid membranes, fold into alpha-helices and disrupt model membrane permeability. A peptide corresponding to the LLP-1 domain of a clade D HIV-1 virus, LLP-1D displayed similar activity to the LLP-1 domain of the clade B virus in all assays, despite a lack of amino acid sequence identity.

Conclusion: These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin. Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

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Related in: MedlinePlus

Sequence and predicted secondary structures of the LLP domains. (A) Wimley-White hydrophobicity plot of TM predicted amino acid sequence of HIVHXB2. Highlighted cylinders show the locations of the LLP domains. A hydrophibicity score could not be calculated for the entire LLP-1 domain due to its location at the extreme c-terminus of TM. (B) Helical wheel diagrams showing the amphipathic nature of each LLP domain. The coloring scheme is from Benner et al. and graphs were generated using a java applet [72]. (C) Primary amino acid sequence of the synthesized peptides used in subsequent experiments which correspond to the LLP-1, -2, and -3 domains of the TM protein.
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Figure 1: Sequence and predicted secondary structures of the LLP domains. (A) Wimley-White hydrophobicity plot of TM predicted amino acid sequence of HIVHXB2. Highlighted cylinders show the locations of the LLP domains. A hydrophibicity score could not be calculated for the entire LLP-1 domain due to its location at the extreme c-terminus of TM. (B) Helical wheel diagrams showing the amphipathic nature of each LLP domain. The coloring scheme is from Benner et al. and graphs were generated using a java applet [72]. (C) Primary amino acid sequence of the synthesized peptides used in subsequent experiments which correspond to the LLP-1, -2, and -3 domains of the TM protein.

Mentions: Three domains have previously been identified in the C-terminus of TM from HIV-1 strain HXB2 (clade B) with homology to natural lytic peptides, such as magainin-2, and to the S4 domain of K+ and Na+ channels [12,14,30]. These domains, identified as LLP-1, LLP-2, and LLP-3 for the order of their discovery, were examined on the Wimley-White (W-W) interfacial hydrophobicity scale for their propensity to partition in lipid membranes (Figure 1A). The W-W hydrophobicity scale is the first experimentally determined hydrophobicity scale based on the transfer of free energies for each amino acid [31]. This scale takes into account contributions from the peptide bonds and side chains when partitioning into membranes. A W-W score greater than zero indicates a propensity to partition into lipid membranes. LLP-3 scored the highest average interfacial hydrophobicity, +3.26 kcal/mol, and is predicted to partition into membranes. LLP-2 possessed an average hydrophobicity score of 0 kcal/mol and based on this score alone LLP-2 would not be expected to partition into membranes. Likewise, LLP-1 would not be expected to partition into membranes with an average interfacial hydrophobicity score of -8.42 kcal/mol.


Viroporin potential of the lentivirus lytic peptide (LLP) domains of the HIV-1 gp41 protein.

Costin JM, Rausch JM, Garry RF, Wimley WC - Virol. J. (2007)

Sequence and predicted secondary structures of the LLP domains. (A) Wimley-White hydrophobicity plot of TM predicted amino acid sequence of HIVHXB2. Highlighted cylinders show the locations of the LLP domains. A hydrophibicity score could not be calculated for the entire LLP-1 domain due to its location at the extreme c-terminus of TM. (B) Helical wheel diagrams showing the amphipathic nature of each LLP domain. The coloring scheme is from Benner et al. and graphs were generated using a java applet [72]. (C) Primary amino acid sequence of the synthesized peptides used in subsequent experiments which correspond to the LLP-1, -2, and -3 domains of the TM protein.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2211469&req=5

Figure 1: Sequence and predicted secondary structures of the LLP domains. (A) Wimley-White hydrophobicity plot of TM predicted amino acid sequence of HIVHXB2. Highlighted cylinders show the locations of the LLP domains. A hydrophibicity score could not be calculated for the entire LLP-1 domain due to its location at the extreme c-terminus of TM. (B) Helical wheel diagrams showing the amphipathic nature of each LLP domain. The coloring scheme is from Benner et al. and graphs were generated using a java applet [72]. (C) Primary amino acid sequence of the synthesized peptides used in subsequent experiments which correspond to the LLP-1, -2, and -3 domains of the TM protein.
Mentions: Three domains have previously been identified in the C-terminus of TM from HIV-1 strain HXB2 (clade B) with homology to natural lytic peptides, such as magainin-2, and to the S4 domain of K+ and Na+ channels [12,14,30]. These domains, identified as LLP-1, LLP-2, and LLP-3 for the order of their discovery, were examined on the Wimley-White (W-W) interfacial hydrophobicity scale for their propensity to partition in lipid membranes (Figure 1A). The W-W hydrophobicity scale is the first experimentally determined hydrophobicity scale based on the transfer of free energies for each amino acid [31]. This scale takes into account contributions from the peptide bonds and side chains when partitioning into membranes. A W-W score greater than zero indicates a propensity to partition into lipid membranes. LLP-3 scored the highest average interfacial hydrophobicity, +3.26 kcal/mol, and is predicted to partition into membranes. LLP-2 possessed an average hydrophobicity score of 0 kcal/mol and based on this score alone LLP-2 would not be expected to partition into membranes. Likewise, LLP-1 would not be expected to partition into membranes with an average interfacial hydrophobicity score of -8.42 kcal/mol.

Bottom Line: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development.These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin.Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biotechnology Research Group, Department of Biology, Florida Gulf Coast University, 10501 FGCU Blvd. S., Fort Myers, FL 33965, USA. jcostin@fgcu.edu

ABSTRACT

Background: Mechanisms by which HIV-1 mediates reductions in CD4+ cell levels in infected persons are being intensely investigated, and have broad implications for AIDS drug and vaccine development. Virally induced changes in membrane ionic permeability induced by lytic viruses of many families contribute to cytopathogenesis. HIV-1 induces disturbances in plasma membrane ion transport. The carboxyl terminus of TM (gp41) contains potential amphipathic alpha-helical motifs identified through their structural similarities to naturally occurring cytolytic peptides. These sequences have been dubbed lentiviral lytic peptides (LLP) -1, -2, and -3.

Results: Peptides corresponding to the LLP domains (from a clade B virus) partition into lipid membranes, fold into alpha-helices and disrupt model membrane permeability. A peptide corresponding to the LLP-1 domain of a clade D HIV-1 virus, LLP-1D displayed similar activity to the LLP-1 domain of the clade B virus in all assays, despite a lack of amino acid sequence identity.

Conclusion: These results suggest that the C-terminal domains of HIV-1 Env proteins may form an ion channel, or viroporin. Increased understanding of the function of LLP domains and their role in the viral replication cycle could allow for the development of novel HIV drugs.

Show MeSH
Related in: MedlinePlus