Localization-based super-resolution microscopy reveals relationship between SARS-CoV2 spike and phosphatidylinositol (4,5): biphosphate

Raut, Prakash; Waters, Hang; Zimmerberg, Joshua; Obeng, Bright; Gosse, Julie A.; Hess, Samuel T.

doi:10.1117/12.2613460

Cited by 7 publications

(8 citation statements)

References 64 publications

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“…Complexes are formed between spikes and neutral lipids [ 55 ], phospholipids [ 56 ], fatty acids [ 45 , 46 , 47 ], biliverdin [ 48 ], and cholesterol [ 57 , 58 ] that contribute to cell–cell fusion [ 59 ] and viral entry [ 60 ]. Other candidate lipid ligands include membrane raft components and gangliosides, which can be accommodated within SARS-CoV-2 NTD structures [ 61 , 62 ], as well as PtdIns(4,5)P 2 , which colocalizes with spikes in the plasma membrane [ 63 ]. Structures of complexes of SARS-CoV-2 spike trimers bound to lipids including fatty acids have been resolved [ 45 , 47 , 64 ] and suggest how cholesterol [ 57 ] could influence viral entry [ 60 ].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Candidates involved in SARS-CoV-2 spike binding and viral entry include phosphatidylcholine, phosphatidylserine (Asandei et al, 2020;Luchini et al, 2021), phosphatidylinositol 3,5-bisphosphate (PtdIns (3,5)P 2 ) (Kang et al, 2020;Ou et al, 2020), and cholesterol (Correa et al, 2021;Wei et al, 2020), which is known to be important for COVID-19 disease progression (Sanders et al, 2021). Spikes are also observed to co-locate with PtdIns(4,5)P 2 in the plasma membrane (Raut et al, 2022). The interaction of linoleic acid within subunit interfaces stabilizes the closed conformation of the prefusion spike (Bangaru et al, 2020;Carrique et al, 2020;Toelzer et al, 2020;Yan et al, 2021), reducing the probability that upturned RBD conformers bind membranes via overlapping sites that are mutated in Omicron subvariants.…”

Section: Discussionmentioning

confidence: 99%

Progressive membrane-binding mechanism of SARS-CoV-2 variant spike proteins

2022

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“…Using proteins allows for genetically encoding the fluorescent label needed for super-resolution [ 94 ]. Genetically encoded PIP 2 sensors are available for PALM imaging [ 43 , 95 ]. PIP 2 is typically measured on the inner leaflet of the plasma membrane, which is not accessible in live cells.…”

Section: Combination Of Lipid and Protein Labeling Using Two-color Su...mentioning

confidence: 99%

“…The genetically encoded PIP 2 sensors are comprised of the PLC-δ PIP 2 binding domain and a genetically encoded PALM protein. This technique was recently used to show the clustering of SARS-CoV-2 (SARS2) spike protein with PIP 2 [ 43 , 96 ]. The spike protein was genetically encoded with dendra2 and the PIP 2 binding domain from PLC-δ with PAmKate.…”

Section: Combination Of Lipid and Protein Labeling Using Two-color Su...mentioning

confidence: 99%

“…PIP 2 also dramatically regulates protein function through protein–lipid interactions, including gating ion channels and trafficking membrane proteins [ 13 , 14 , 15 , 16 , 17 , 35 , 36 , 37 , 38 , 39 ]. Here we use these biophysical properties and recent findings from super-resolution imaging [ 7 , 22 , 40 , 41 , 42 , 43 ] to establish basic models for proteins moving nanoscopic distances in the membrane. We define cholesterol-regulated proteins (CRPs) and their activation mechanism by CRP localization.…”

Section: Introductionmentioning

confidence: 99%

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Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging

Yuan

Hansen²

2023

Membranes

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Cholesterol and phosphatidyl inositol 4,5-bisphosphate (PIP2) are hydrophobic molecules that regulate protein function in the plasma membrane of all cells. In this review, we discuss how changes in cholesterol concentration cause nanoscopic (<200 nm) movements of membrane proteins to regulate their function. Cholesterol is known to cluster many membrane proteins (often palmitoylated proteins) with long-chain saturated lipids. Although PIP2 is better known for gating ion channels, in this review, we will discuss a second independent function as a regulator of nanoscopic protein movement that opposes cholesterol clustering. The understanding of the movement of proteins between nanoscopic lipid domains emerged largely through the recent advent of super-resolution imaging and the establishment of two-color techniques to label lipids separate from proteins. We discuss the labeling techniques for imaging, their strengths and weakness, and how they are used to reveal novel mechanisms for an ion channel, transporter, and enzyme function. Among the mechanisms, we describe substrate and ligand presentation and their ability to activate enzymes, gate channels, and transporters rapidly and potently. Finally, we define cholesterol-regulated proteins (CRP) and discuss the role of PIP2 in opposing the regulation of cholesterol, as seen through super-resolution imaging.

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Localization-based super-resolution microscopy reveals relationship between SARS-CoV2 spike and phosphatidylinositol (4,5): biphosphate

Cited by 7 publications

References 64 publications

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

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

Progressive membrane-binding mechanism of SARS-CoV-2 variant spike proteins

Cholesterol Regulation of Membrane Proteins Revealed by Two-Color Super-Resolution Imaging

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