Multifaceted membrane binding head of the SARS-CoV-2 spike protein

Tran, Anh; Kervin, Troy A.; Overduin, Michael

doi:10.1016/j.crstbi.2022.05.001

Cited by 7 publications

(13 citation statements)

References 85 publications

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“…The copyright holder for this preprint this version posted December 23, 2022. ; https://doi.org/10.1101/2022.12.23.521840 doi: bioRxiv preprint vitro and in vivo loss-of-function mutagenesis analyses. Our results suggest that hAtg3 exploits a multifaceted membrane-association mechanism [32][33][34][35][36][37][38] to position the catalytic residue Cys264 at the membrane surface and bring substrates of LC3 and PE lipids in proximity to promote LC3-PE conjugation. In addition, NMR hydrogen/deuterium exchange studies revealed that the catalytic loop and following α-helix of hAtg3 are conformationally dynamic in aqueous solution and are conducive to interaction with the membrane, even though the general hAtg3 core structure is similar to those previously reported for yeast and Arabidopsis thaliana.…”

mentioning

confidence: 87%

Translating Membrane Geometry into Protein Function: Multifaceted Membrane Interactions of Human Atg3 Promote LC3-Phosphatidylethanolamine Conjugation during Autophagy

Tyndall

Bui

et al. 2022

Preprint

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Autophagosome formation is the hallmark of macroautophagy (herein referred to as autophagy) and requires the covalent conjugation of LC3 proteins (or Atg8 in yeast) to the amino headgroup of PE (phosphatidylethanolamine) lipids. Atg3 is an enzyme that catalyzes the final step of this reaction by transferring LC3 from an LC3-Atg3 intermediate to PEs in targeted membranes. Here, we determine the solution structure of human Atg3 (hAtg3) and demonstrate that the catalytically important regions of hAtg3 are conformationally dynamic. Furthermore, we reveal that these regions and hAtg3′s N-terminal membrane curvature-sensing amphipathic helix concurrently interact with the membrane. These structural studies indicate that hAtg3 exploits a multifaceted membrane-association mechanism to position its catalytic center at the membrane surface and to bring the reaction substrates of LC3 and PE lipids to proximity for effective LC3-PE conjugation. In addition, our studies demonstrate that the interaction of the His266 residue with the membrane is primarily responsible for hAtg3′s pH-dependent activity. Our investigations advance an emerging concept that the interactions of Atg3 with the highly curved membrane rims of the phagophore spatially regulate autophagosome biogenesis.

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mentioning

confidence: 87%

Translating Membrane Geometry into Protein Function: Multifaceted Membrane Interactions of Human Atg3 Promote LC3-Phosphatidylethanolamine Conjugation during Autophagy

Tyndall

Bui

et al. 2022

Preprint

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“…The F486V mutation also appears to help evade neutralizing antibodies, and while this substitution retains membrane binding, it does so with reduced propensity. The deletion of H69 and V70 in the BA.3 and BA.4/5 NTDs (which also features in BA.1) compromises a putative pH switch that could favour endocytic entry [ 11 ], while the proximal G72 and N74 residues exhibit increased membrane binding propensities ( Figure 4 ).…”

Section: Resultsmentioning

confidence: 99%

“…The spike protein forms a trimer, which amplifies the effects of mutations three-fold. The spike head, where most Omicron mutations are found, is composed of a N-terminal domain (NTD) and receptor binding domain (RBD), both of which present membrane binding surfaces in their closed and open states [ 10 , 11 ]. Spike opening involves raising of the RBD, whereupon it can recognize an ACE-2 molecule on a host cell through the receptor binding motif (RBM).…”

Section: Introductionmentioning

confidence: 99%

“…The latter is trained to identify lipid binding surfaces and calculates membrane binding propensities for each residue in a protein structure. We previously used MODA to discover membrane binding sites in bacterial and viral trafficking proteins [ 35 , 36 ], eukaryotic membrane readers [ 37 , 38 ], and spike proteins [ 10 , 11 ]. Here, we use this approach to reveal how Omicron subvariant mutations affect the spike’s abilities to attract and engage membranes.…”

Section: Introductionmentioning

confidence: 99%

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SARS-CoV-2 Omicron Subvariants Balance Host Cell Membrane, Receptor, and Antibody Docking via an Overlapping Target Site

Overduin

Bhat

Kervin

2023

Viruses

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Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are emerging rapidly and offer surfaces that are optimized for recognition of host cell membranes while also evading antibodies arising from vaccinations and previous infections. Host cell infection is a multi-step process in which spike heads engage lipid bilayers and one or more angiotensin-converting enzyme 2 (ACE-2) receptors. Here, the membrane binding surfaces of Omicron subvariants are compared using cryo-electron microscopy (cEM) structures of spike trimers from BA.2, BA.2.12.1, BA.2.13, BA.2.75, BA.3, BA.4, and BA.5 viruses. Despite significant differences around mutated sites, they all maintain strong membrane binding propensities that first appeared in BA.1. Both their closed and open states retain elevated membrane docking capacities, although the presence of more closed than open states diminishes opportunities to bind receptors while enhancing membrane engagement. The electrostatic dipoles are generally conserved. However, the BA.2.75 spike dipole is compromised, and its ACE-2 affinity is increased, and BA.3 exhibits the opposite pattern. We propose that balancing the functional imperatives of a stable, readily cleavable spike that engages both lipid bilayers and receptors while avoiding host defenses underlies betacoronavirus evolution. This provides predictive criteria for rationalizing future pandemic waves and COVID-19 transmissibility while illuminating critical sites and strategies for simultaneously combating multiple variants.

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“…To identify the bilayer-interacting surfaces of each spike ectodomain, the membrane-binding propensities of >500,000 residues within 158 spike structures from SARS-CoV-1, 12 SARS-CoV-2 variants, as well as pangolin and bat homologs were measured using the MODA program (Bissig et al, 2013;Kufareva et al, 2014). The resulting model builds on our earlier mapping of the membrane-binding sites in wild-type SARS-CoV-2 spike trimers (Tran et al, 2022) and provides a unifying explanation for how betacoronaviruses interact with any lipid bilayer.…”

Section: Spike Heads Contain Conserved Membrane-binding Sitesmentioning

confidence: 99%