Conserved arginine residue in the membrane-spanning domain of HIV-1 gp41 is required for efficient membrane fusion

Long, Yufei; Meng, Fanxia; Kondo, Naoyuki; Iwamoto, Aikichi; Matsuda, Zene

doi:10.1007/s13238-011-1051-0

Cited by 24 publications

(28 citation statements)

References 32 publications

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“…An interesting observation correlated with the findings of Long, Y showed that Arginine (R) was most frequently associated amino acid (8). In all the 10 rules deduced Arginine was found to be associated with all the amino acids.…”

Section: Rules Framed For All the Classes Evaluated Togethersupporting

confidence: 84%

Association Rule Mining to Deduce the Most Frequently Occurring Amino Acid Patterns in HIV

Pant¹,

Pant²,

Negi³

2012

IJCA

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HIV is one of the most dreaded diseases of the century. Throughout the world efforts are underway to develop new vaccines and design new drugs so as to combat this viral menace. In an effort to probe deeper into the functioning of these viruses we present association based rules formulation so as to decipher the most frequently occurring amino acids in these viruses. This is a novel attempt of its kind since we are attempting to find put the most informative association rules using Apriori algorithm implemented through WEKA. The information generated can be of great use to molecular biologists and drug designers since the associated amino acids can be a very good drug targets.Our findings suggest that L-Selenocysteine and L-Pyrrolysine are most frequently associated amino acids in the 4 classes of virulent proteins analyzed for association rules and Cyteine and Arginine show the strongest association in one of the class analyzed i.e. Gp41. Hence these can be potential drug candidates.

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Section: Rules Framed For All the Classes Evaluated Togethersupporting

confidence: 84%

Association Rule Mining to Deduce the Most Frequently Occurring Amino Acid Patterns in HIV

Pant¹,

Pant²,

Negi³

2012

IJCA

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“…The membrane spanning domain (MSD) of gp41 is of great interest as it is responsible for both anchoring gp41 in the bilayer and for playing a role in fusion, according to truncation studies [3,4]. Mutagenesis has also shown that the specific sequence of the twenty-seven residue MSD is important for membrane fusion [5–11]. The MSD houses the GXXXG motif, postulated to mediate transmembrane helical interactions, and the charged residues K681, R694, R705, and R707 (Table 1) [3–14].…”

Section: Introductionmentioning

confidence: 99%

“…Relatively large water defects have been studied by solid-state NMR and have also been observed in various simulation systems involving guanidinium ions, arginine analogs, and arginine containing transmembrane proteins (both β -barrels and α-helices) in various lipids [20,21,23,26–31]. It has not been previously investigated if HIV-1 gp41 MSD displays a water defect in the native spike complex, but an arginine at position 694 (HXBc2 sequence) is required for full fusion [11,4]. Therefore, it stands to reason that if a water defect is present due to R694, the defect may play a role in fusion as well.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the water defect at the HIV-1 gp41 membrane spanning domain in bilayers with and without cholesterol using molecular simulations

Baker

Gangupomu²,

Abrams

2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The membrane spanning domain (MSD) of human immunodeficiency virus 1 (HIV-1) envelope glycoprotein gp41 is important for fusion and infection. We used molecular dynamics (MD) simulations (3.4 μs total) to relate membrane and peptide properties that lead to water solvation of the α-helical gp41 MSD’s midspan arginine in pure dipalmitoylphosphatidylcholine (DPPC) and in 50/50 DPPC/cholesterol membranes. We find that the midspan arginine is solvated by water that penetrates the inner leaflet, leading to a so-called water defect. The water defect is surprisingly robust across initial conditions and membrane compositions, but the presence of cholesterol modulates its behavior in several key ways. In the cholesterol-containing membranes, fluctuations in membrane thickness and water penetration depth are localized near the midspan arginine, and the MSD helices display a tightly regulated tilt angle. In the cholesterol-free membranes, thickness fluctuations are not as strongly correlated to the peptide position and tilt angles vary significantly depending on protein position relative to boundaries between domains of differing thickness. Cholesterol in an HIV-1 viral membrane is required for infection. Therefore, this work suggests that the colocalized water defect and membrane thickness fluctuations in cholesterol-containing viral membranes play an important role in fusion by bringing the membrane closer to a stability limit that must be crossed for fusion to occur.

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“…However, the role of these motifs during virus-cell fusion is not yet clear. Furthermore, a recent study showed that mutating the Arg residue within the intact protein did not affect the expression or location of Env, but rather, affected its fusion activity (38). …”

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confidence: 99%

HIV-1 gp41 Transmembrane Domain Interacts with the Fusion Peptide: Implication in Lipid Mixing and Inhibition of Virus–Cell Fusion

et al. 2012

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Fusion of the human immunodeficiency virus (HIV) with target cells is mediated by the gp41 subunit of the envelope protein. Mutation and deletion studies within the transmembrane domain (TMD) of intact gp41 influenced its fusion activity. In addition, current models suggest that the TMD is in proximity with the fusion peptide (FP) at the late fusion stages, but there are no direct experimental data to support this hypothesis. Here, we investigated the TMD focusing on two regions: the N-terminal containing the GxxxG motif and the C-terminal containing the GLRI motif, which is conserved among the TMDs of HIV and the T-cell receptor. Studies utilizing the ToxR expression system combined with synthetic peptides and their fluorescent analogues derived from TMD revealed that the GxxxG motif is important for TMD self-association, whereas the Cterminal region is for its heteroassociation with FP. Functionally, all three TMD peptides induced lipid mixing that was enhanced significantly upon mixing with FP. Furthermore, the TMD peptides inhibited virus−cell fusion apparently through their interaction with their endogenous counterparts. Notably, the R2E mutant (in the GLRI) was significantly less potent than the two others. Overall, our findings provide experimental evidence that HIV-1 TMD contributes to membrane assembly and function of the HIV-1 envelope. Owing to similarities between functional domains within viruses, these findings suggest that the TMDs and FPs may contribute similarly in other viruses as well.

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Conserved arginine residue in the membrane-spanning domain of HIV-1 gp41 is required for efficient membrane fusion

Cited by 24 publications

References 32 publications

Association Rule Mining to Deduce the Most Frequently Occurring Amino Acid Patterns in HIV

Association Rule Mining to Deduce the Most Frequently Occurring Amino Acid Patterns in HIV

Characterization of the water defect at the HIV-1 gp41 membrane spanning domain in bilayers with and without cholesterol using molecular simulations

HIV-1 gp41 Transmembrane Domain Interacts with the Fusion Peptide: Implication in Lipid Mixing and Inhibition of Virus–Cell Fusion

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