Theoretically Determined Three-Dimensional Structures for Amphipathic Segments of the HIV-1 gp41 Envelope Protein

Venable, Richard M.; Pastor, Richard W.; Brooks, Bernard R.; Carson, Frederick W.

doi:10.1089/aid.1989.5.7

Cited by 93 publications

(66 citation statements)

References 56 publications

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“…In contrast, the palmitoylated cysteine residues in the HIV-1 envelope cytoplasmic tail are about 59 and 132 amino acids away from the proposed membrane-spanning domain (41). However, there are two amphipathic regions in the cytoplasmic domain of the HIV envelope proteins, and it has been proposed that they could associate with the plasma membrane (42,43). The cysteine residues required for the palmitoylation of the HIV envelope protein are very close to these amphipathic regions.…”

Section: Discussionmentioning

confidence: 97%

The human and simian immunodeficiency virus envelope glycoprotein transmembrane subunits are palmitoylated.

Yang

Spies

Compans

1995

Proc. Natl. Acad. Sci. U.S.A.

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The envelope proteins of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) were found to be modified by fatty acylation of the transmembrane protein subunit gp4l. The precursor gpl60 was also palmitoylated prior to its cleavage into the gpl20 and gp4l subunits. The palmitic acid label was sensitive to treatment with hydroxylamine or 2-mercaptoethanol, indicating that the linkage is through a thioester bond. Treatment with cycloheximide did not prevent the incorporation of [3H]palmitic acid into the HIV envelope protein, indicating that palmitoylation is a posttranslation modification. In contrast to other glycoproteins, which are palmitoylated at cysteine residues within or close to the membrane-spanning hydrophobic domain, the palmitoylation of the HIV-1 envelope proteins occurs on two cysteine residues, Cys-764 and Cys-837, which are 59 and 132 amino acids, respectively, from the proposed membrane-spanning domain of gp4l. Sequence comparison revealed that one of these residues (Cys-764) is conserved in the cytoplasmic domains of almost all HIV-1 isolates and is located very close to an amphipathic region which has been postulated to bind to the plasma membrane.

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Section: Discussionmentioning

confidence: 97%

The human and simian immunodeficiency virus envelope glycoprotein transmembrane subunits are palmitoylated.

Yang

Spies

Compans

1995

Proc. Natl. Acad. Sci. U.S.A.

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“…Mutations in this domain may enhance Env fusion activity, but viral infectivity is greatly reduced in infected peripheral blood mononuclear cells, macrophages, and most T-cell lines (11,13,15,49). The three highly conserved amphipathic ␣-helical segments, designated lentiviral lytic peptide 1 (LLP)-1, LLP-2, and LLP-3, located in the C terminus of the cytoplasmic tail are thought to be associated with the inner surfaces of viral and cellular membranes (33,45). We previously showed that the multimerization potential and membrane binding ability of the cytoplasmic tail may play a crucial role in virus replication (3,5,7,28) and that the N-terminal segment of LLP-1 contains a structural determinant critical for modulating Env stability (27).…”

mentioning

confidence: 99%

Effect of Extension of the Cytoplasmic Domain of Human Immunodeficiency Type 1 Virus Transmembrane Protein gp41 on Virus Replication

Chan

Wang

Lin

et al. 2004

J Virol

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The biological significance of the presence of a long cytoplasmic domain in the envelope (Env) transmembrane protein gp41 of human immunodeficiency virus type 1 (HIV-1) is still not fully understood. Here we examined the effects of cytoplasmic tail elongation on virus replication and characterized the role of the C-terminal cytoplasmic tail in interactions with the Gag protein. Extensions with six and nine His residues but not with fewer than six His residues were found to severely inhibit virus replication through decreased Env electrophoretic mobility and reduced Env incorporation compared to the wild-type virus. These two mutants also exhibited distinct N glycosylation and reduced cell surface expression. An extension of six other residues had no deleterious effect on infectivity, even though some mutants showed reduced Env incorporation into the virus and/or decreased cell surface expression. We further show that these elongated cytoplasmic tails in a format of the glutathione S-transferase fusion protein still interacted effectively with the Gag protein. In addition, the immediate C terminus of the cytoplasmic tail was not directly involved in interactions with Gag, but the region containing the last 13 to 43 residues from the C terminus was critical for Env-Gag interactions. Taken together, our results demonstrate that HIV-1 Env can tolerate extension at its C terminus to a certain degree without loss of virus infectivity and Env-Gag interactions. However, extended elongation in the cytoplasmic tail may impair virus infectivity, Env cell surface expression, and Env incorporation into the virus.

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“…The C terminus of the cytoplasmic tail may play a role in viral uncoating or penetration of the viral core into host cells (18). The large helical hydrophobic moments of the two segments spanning residues 828 -856 and 770 -795 (19,20), termed lentiviral lytic peptide (LLP)-1 and LLP-2, respectively, may have membrane-related functions (19). Structural modeling of these two regions reveals a high potential to form amphipathic ␣-helices (19 -21).…”

mentioning

confidence: 99%

Multimerization Potential of the Cytoplasmic Domain of the Human Immunodeficiency Virus Type 1 Transmembrane Glycoprotein gp41

Lee¹,

Wang²,

Liang³

et al. 2000

Journal of Biological Chemistry

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We previously demonstrated that an envelope mutant of human immunodeficiency virus type 1 lacking the entire cytoplasmic domain interferes in trans with the production of infectious virus by inclusion of the mutant envelope into the wild-type envelope complex. We also showed that the envelope incorporation into virions is not affected when the wild-type envelope is coexpressed with the mutant envelope. These results suggest that an oligomeric structure of the cytoplasmic domain is functionally required for viral infectivity. To understand whether the cytoplasmic domain of human immunodeficiency virus type 1 transmembrane protein gp41 has the potential to self-assemble as an oligomer, in the present study we fused the coding sequence of the entire cytoplasmic domain at 3 to the Escherichia coli malE gene, which encodes a monomeric maltose-binding protein. The expressed fusion protein was examined by chemical cross-linking, sucrose gradient centrifugation, and gel filtration. The results showed that the cytoplasmic domain of gp41 assembles into a high-ordered structural complex. The intersubunit interaction of the cytoplasmic domain was also confirmed by a mammalian two-hybrid system that detects protein-protein interactions in eucaryotic cells. A cytoplasmic domain fragment expressed in eucaryotic cells was pulled down by glutathione-Sepharose 4B beads via its association with another cytoplasmic domain fragment fused to the C terminus of the glutathione S-transferase moiety. We also found that sequences encompassing the lentiviral lytic peptide-1 and lentiviral lytic peptide-2, which are located within residues 828 -856 and 770 -795, respectively, play a critical role in cytoplasmic domain selfassembly. Taken together, the results from the present study indicate that the cytoplasmic domain of gp41 by itself is sufficient to assemble into a multimeric structure. This finding supports the hypothesis that a multimeric form of the gp41 cytoplasmic domain plays a crucial role in virus infectivity.

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Theoretically Determined Three-Dimensional Structures for Amphipathic Segments of the HIV-1 gp41 Envelope Protein

Cited by 93 publications

References 56 publications

The human and simian immunodeficiency virus envelope glycoprotein transmembrane subunits are palmitoylated.

The human and simian immunodeficiency virus envelope glycoprotein transmembrane subunits are palmitoylated.

Effect of Extension of the Cytoplasmic Domain of Human Immunodeficiency Type 1 Virus Transmembrane Protein gp41 on Virus Replication

Multimerization Potential of the Cytoplasmic Domain of the Human Immunodeficiency Virus Type 1 Transmembrane Glycoprotein gp41

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