Rafting through the palms: S-acylation of SARS-CoV-2 spike protein induces lipid reorganization

Understanding fusion mechanisms employed by SARS-CoV-2 spike protein entails realistic transmembrane domain (TMD) models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we propose a comprehensive computational framework to model the spike TMD only based on its primary structure. We performed amino acid sequence pattern matching and compared the molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and selected an appropriate template for homology modeling. We then iteratively built a model of spike TMD, adjusting “dynamic MHP portraits” and residue variability motifs. The stability of this model, with and without palmitoyl modifications downstream of the TMD, and several alternative configurations (including a recent NMR structure), was tested in all-atom molecular dynamics simulations in a POPC bilayer mimicking the viral envelope. Our model demonstrated unique stability under the conditions applied and conforms to known basic principles of TM helix packing. The original computational framework looks promising and could potentially be employed in the construction of 3D models of TM trimers for a wide range of membrane proteins.

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Section: Discussionmentioning

confidence: 99%

A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain

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Nolde

et al. 2022

IJMS

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“…However, due to limitations of the MD simulations performed such as the single-component POPC bilayer and elevated temperature, fine-tuning of the lipid environment due to palmitoylation as well as its functional interpretation is not fully accessible in our modelling framework and should be further investigated. Apparently, such effects can be observed in lipid bilayers more complex in composition than POPC; some recent experimental data demonstrate the importance of this issue (Vilmen et al, 2021) Seeing that the proposed TMD model has been created in silico and does not directly rely on experimental structural data, questioning its accuracy and level of similarity to other models would not be unjustified. As far as accuracy is concerned, only one structure of the TMD has been reported, which was obtained by NMR spectroscopy in lipid-detergent bicelles (Fu and Chou, 2021).…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A uniquely stable trimeric model of SARS-CoV-2 spike transmembrane domain

Aliper

Крылов

Nolde

et al. 2022

Preprint

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The spike (S) protein of SARS-CoV-2 effectuates membrane fusion and virus entry into target cells. Its transmembrane domain (TMD) represents a homotrimer of α-helices anchoring the spike in the viral envelope. Although S-protein models available to date include the TMD, its precise configuration was given brief consideration. Understanding viral fusion entails realistic TMD models, while no reliable approaches towards predicting the 3D structure of transmembrane (TM) trimers exist. Here, we propose a comprehensive computational framework to model the spike TMD (S-TMD) based solely on its primary structure. First, we performed amino acid sequence pattern matching and compared molecular hydrophobicity potential (MHP) distribution on the helix surface against TM homotrimers with known 3D structures and thus selected the TMD of the tumour necrosis factor receptor 1 (TNFR-1) for subsequent template-based modelling. We then iteratively built an all-atom homotrimer model of S-TMD based on "dynamic MHP portraits" and residue variability motifs. In this model each helix possessed two overlapping interfaces interacting with either of the remaining helices, which include conservative residues I1216, F1220, I1227, M1229, and M1233. Finally, the stability of this and several alternative models (including a recent NMR structure) and a set of mutant forms was tested in all-atom molecular dynamics (MD) simulations in a POPC bilayer mimicking the viral envelope membrane. Unlike other configurations, our model trimer remained extraordinarily tightly packed over a microsecond-range MD and retained its stability when palmitoylated in accordance with experimental data. Palmitoylation had no significant impact on the TMD conformation nor the way in which the lipid bilayer was perturbed in the presence of the trimer. Overall, the resulting model of S-TMD conforms to known basic principles of TM helix packing and will be further used to explore the complex machinery of membrane fusion from a broader perspective beyond the TMD.

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“…S-acylation of the spike protein by ZDHHC20 is essential for SARS-CoV-2 infectivity, stabilizing the spike protein trimer and facilitating its interaction with lipid bilayers (Wu et al 2021 ). It was also found that the S-acylation of spike protein triggers cholesterol/sphingolipid-rich raft-like domains to form, enabling membrane fusion (Vilmen et al 2021 ; Mesquita et al 2021 ). The palmitoylation and its association to a raft-like domain protect it from degradation (Vilmen et al 2021 ).…”

Section: Lipidation Of Protein and Membrane Fusionmentioning

confidence: 99%

“…It was also found that the S-acylation of spike protein triggers cholesterol/sphingolipid-rich raft-like domains to form, enabling membrane fusion (Vilmen et al 2021 ; Mesquita et al 2021 ). The palmitoylation and its association to a raft-like domain protect it from degradation (Vilmen et al 2021 ). The palmitoylation of SARS‐CoV‐2 spike protein is critical for S‐mediated syncytia formation and SARS‐CoV‐2 pseudo-virus particle entry (Li et al 2022 ).…”

Section: Lipidation Of Protein and Membrane Fusionmentioning

confidence: 99%

Lipid and Lipidation in Membrane Fusion

et al. 2022

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Membrane fusion plays a lead role in the transport of vesicles, neurotransmission, mitochondrial dynamics, and viral infection. There are fusion proteins that catalyze and regulate the fusion. Interestingly, various types of fusion proteins are present in nature and they possess diverse mechanisms of action. We have highlighted the importance of the functional domains of intracellular heterotypic fusion, homotypic endoplasmic reticulum (ER), homotypic mitochondrial, and type-I viral fusion. During intracellular heterotypic fusion, the SNAREs and four-helix bundle formation are prevalent. Type-I viral fusion is controlled by the membrane destabilizing properties of fusion peptide and six-helix bundle formation. The ER/mitochondrial homotypic fusion is controlled by GTPase activity and the membrane destabilization properties of the amphipathic helix(s). Although the mechanism of action of these fusion proteins is diverse, they have some similarities. In all cases, the lipid composition of the membrane greatly affects membrane fusion. Next, examples of lipidation of the fusion proteins were discussed. We suggest that the fatty acyl hydrophobic tail not only acts as an anchor but may also modulate the energetics of membrane fusion intermediates. Lipidation is also important to design more effective peptide-based fusion inhibitors. Together, we have shown that membrane lipid composition and lipidation are important to modulate membrane fusion. Graphical Abstract

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Rafting through the palms: S-acylation of SARS-CoV-2 spike protein induces lipid reorganization

Cited by 5 publications

References 10 publications

A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain

A Uniquely Stable Trimeric Model of SARS-CoV-2 Spike Transmembrane Domain

A uniquely stable trimeric model of SARS-CoV-2 spike transmembrane domain

Lipid and Lipidation in Membrane Fusion

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