Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

Ra, Murphy; Samal, Alexandra B.; Vlach, Jiří; Saad, Jamil S.

doi:10.1016/j.str.2017.09.010

Cited by 44 publications

(62 citation statements)

References 72 publications

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“…The inter-helical distances at the MPER and CT sequences reflect the differing ability of these regions to open and allow the entry of water and ions into the trimer core (see below). The MPER region remains very stable and tightly packed with stable COM distances between neighboring peptides (~1.2 nm), consistent with experimental observations of the known α-helical character of MPER peptides (65), residue-specific NMR relaxation rates (24), and the observed flexibility of CT residues 707-751 (69). Minor increases in COM distance were observed in the MPER region, persisting for at most 100 ns before returning to a tightly packed state ( Figure S7).…”

Section: Dynamics Of the Tmdsupporting

confidence: 85%

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

Hollingsworth

Lemkul

Bevan

2018

Preprint

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The gp41 transmembrane domain (TMD) of the envelope glycoprotein (Env) of the human immunodeficiency virus (HIV) modulates the conformation of the viral envelope spike, the only druggable target on the surface of the virion. Understanding of TMD dynamics is needed to better probe and target Env with small molecule and antibody therapies. However, little is known about TMD dynamics due to difficulties in describing native membrane properties. Here, we performed atomistic molecular dynamics simulations of a trimeric, prefusion TMD in a model, asymmetric viral membrane that mimics the native viral envelope. We found that water and chloride ions permeated the membrane and interacted with the highly conserved arginine bundle, (R696) 3 , at the center of the membrane and influenced TMD stability by creating a network of hydrogen bonds and electrostatic interactions. We propose that this (R696) 3 -water -anion network plays an important role in viral fusion with the host cell by modulating protein conformational changes within the membrane. Additionally, R683 and R707 at the exofacial and cytofacial membrane-water interfaces, respectively, are anchored in the lipid headgroup region and serve as a junction point for stabilization of the termini. The membrane thins as a result of the tilting of the TMD trimer, with nearby lipids increasing in volume, leading to an entropic driving force for TMD conformational change. These results provide additional detail and perspective on the influence of certain lipid types on TMD dynamics and rationale for targeting key residues of the TMD for therapeutic design. These insights into the molecular details of TMD membrane anchoring will build towards a greater understanding of dynamics that lead to viral fusion with the host cell.

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Section: Dynamics Of the Tmdsupporting

confidence: 85%

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

Hollingsworth

Lemkul

Bevan

2018

Preprint

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“…In this study, we used NMR to obtain high-resolution information of the HIV-1 Env CT folding in the context of the TMD and lipid bilayer. We find that the CT adopts a structure different from the previous model 19 that can explain the physical coupling between the CT and the ectodomain.…”

contrasting

confidence: 72%

“…1a). The LLP2 is not a long continuous helix as previously proposed 19 ; instead it forms two helices, designated H1 (residues 741-764) and H2 (residues 769-786), adopting a ring-like structure around the C-terminal region of the TMD trimer. The three H1s make direct contacts with the TMD trimer to form an inner ring around the TMD (Fig.…”

Section: Resultsmentioning

confidence: 72%

“…1a): a loop, commonly known as the Kennedy sequence (KS), followed by three segments predicted to form amphipathic α-helices, named lentivirus lytic peptide 2 (LLP2), LLP3, and LLP1 17 . Earlier studies suggested that the CT forms three membrane-bound amphipathic helices in an extended conformation 19,20 . These structures are very informative about the secondary structures of the CT, but they fall short of explaining how truncation in the CT can influence the antigenic structure of the ectodomain on the opposite side of the membrane 5,21,22 .…”

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confidence: 99%

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Structural basis of transmembrane coupling of the HIV-1 envelope glycoprotein

Piai

Cai

et al. 2020

Nat Commun

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The prefusion conformation of HIV-1 envelope protein (Env) is recognized by most broadly neutralizing antibodies (bnAbs). Studies showed that alterations of its membrane-related components, including the transmembrane domain (TMD) and cytoplasmic tail (CT), can reshape the antigenic structure of the Env ectodomain. Using nuclear magnetic resonance (NMR) spectroscopy, we determine the structure of an Env segment encompassing the TMD and a large portion of the CT in bicelles. The structure reveals that the CT folds into amphipathic helices that wrap around the C-terminal end of the TMD, thereby forming a support baseplate for the rest of Env. NMR dynamics measurements provide evidences of dynamic coupling across the TMD between the ectodomain and CT. Pseudovirus-based neutralization assays suggest that CT-TMD interaction preferentially affects antigenic structure near the apex of the Env trimer. These results explain why the CT can modulate the Env antigenic properties and may facilitate HIV-1 Env-based vaccine design.

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“…We chose an approximate azimuthal orientation based on connections emanating from the C-terminal helices of the BG505 SOSIP.664 model ( Fig. 2B) The CT, which includes several membrane-associated, amphipathic helices [35], is completely disordered, as expected in the absence of a lipid bilayer.…”

Section: Model Buildingmentioning

confidence: 99%

Cryo-EM structure of full-length HIV-1 Env bound with the Fab of antibody PG16

Pan¹,

Peng²,

Chen³

2019

Preprint

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The HIV-1 envelope protein (Env) is the target of neutralizing antibodies and the template for vaccine immunogen design. The dynamic conformational equilibrium of trimeric Env influences its antigenicity and potential immunogenicity. Antibodies that bind at the trimer apex stabilize a "closed" conformation characteristic of the most difficult to neutralize isolates. A goal of vaccine development is therefore to mimic the closed conformation in a designed immunogen. A disulfide-stabilized, trimeric Env ectodomain --the "SOSIP" construct --has many of the relevant properties; it is also particularly suitable for structure determination. Some singlemolecule studies have, however, suggested that the SOSIP trimer is not a good representation of Env on the surface of a virion or an infected cell. We isolated Env (fully cleaved to gp120 and gp41) from the surface of expressing cells using tagged, apex-binding Fab PG16 and determined the structure of the PG16-Env complex by cryo-EM to an overall resolution of 4.6 Å.Placing the only purification tag on the Fab ensured that the isolated Env was continuously stabilized in its closed, native conformation. The Env structure in this complex corresponds closely to the SOSIP structures determined by both x-ray crystallography and cryo-EM.Although the membrane-interacting elements are not resolved in our reconstruction, we can make inferences about the connection between ectodomain and membrane-proximal external region (MPER) by reference to the published cryo-tomography structure of an Env "spike" and the NMR structure of the MPER-transmembrane segment. We discuss these results in view of the conflicting interpretations in the literature.

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Solution Structure and Membrane Interaction of the Cytoplasmic Tail of HIV-1 gp41 Protein

Cited by 44 publications

References 72 publications

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

Structural basis of transmembrane coupling of the HIV-1 envelope glycoprotein

Cryo-EM structure of full-length HIV-1 Env bound with the Fab of antibody PG16

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