Measles and Nipah virus assembly: Specific lipid binding drives matrix polymerization

Abstract

Measles virus, Nipah virus, and multiple other paramyxoviruses cause disease outbreaks in humans and animals worldwide. The paramyxovirus matrix (M) protein mediates virion assembly and budding from host cell membranes. M is thus a key target for antivirals, but few high-resolution structures of paramyxovirus M are available, and we lack the clear understanding of how viral M proteins interact with membrane lipids to mediate viral assembly and egress that is needed to guide antiviral design. Here, we reveal that M proteins associate with phosphatidylserine and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] at the plasma membrane. Using x-ray crystallography, electron microscopy, and molecular dynamics, we demonstrate that PI(4,5)P 2 binding induces conformational and electrostatic changes in the M protein surface that trigger membrane deformation, matrix layer polymerization, and virion assembly.

The Ebola virus VP40 matrix undergoes endosomal disassembly essential for membrane fusion

“…VP40 detachment from viral envelope is caused by a disruption of electrostatic interactions between VP40 and negatively charged lipids in the viral envelope, which have experimentally been demonstrated and attributed to a basic patch of lysine residues decorating the VP40 C-termini [48][49][50][51] . Considering that matrix protein assembly of other RNA viruses relies on electrostatic interactions with negatively charged lipids 60 , we propose that pH-mediated matrix disassembly is a general mechanism critical for viral uncoating. Notably, pH-driven structural remodeling of viruses has so far only been shown and extensively studied for influenza A virus 61 , which is known to encode the viral ion channel M2 (reviewed here 62 ).…”

CHARMM-GUI Membrane Builder: Past, Current, and Future Developments and Applications

“…Viruses generally have a membrane structure to keep the nucleic acids inside the viral vesicle. Consequently, studies have focused on the membrane proteins that mediate cell binding (such as spike protein gp120) and viral membrane proteins (such as matrix protein and envelope protein E). − Choi et al studied the dynamics of the fully glycosylated full-length spike protein of SARS-CoV-2 anchored in a viral lipid bilayer. , Spike protein is important for host cell entry by binding to ACE2 protein in the host cell membrane. MD simulations reveal the spike protein orientation and dynamics characterized by rigid bodies of different parts (Figure D).…”

Specific targeting and clustering of Phosphatidylserine lipids by RSV M protein is critical for virus particle production

“…Recently, it was reported that Paramyxovirus Nipah and Measles M proteins interact with negatively charged PS lipids, and that PI(4,5)P2 significantly enhances this interaction (29).…”

“…In vitro studies have shown that RSV M protein interacts with lipid monolayers with neutral lipid compositions (DOPC/DPPC/cholesterol and DOPC/SM/cholesterol), and this interaction does not appear to be affected by the hydrophobic effect or the presence of cholesterol (28). More recent research has revealed that a specific set of lipids is required for M protein lattice formation in some paramyxoviruses, such as Nipah and measles (29). These viruses require phosphatidylserine (PS) and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) for M protein interaction with lipids and M protein oligomerization.…”

“…Overall, the lipid interactions of M proteins from different enveloped viruses appear to be diverse, but several common themes have emerged. Many of these M proteins associate with lipid rafts and interact with phospholipids, such as PS and PI(4,5)P2 (25,(29)(30)(31)(32). These interactions appear to play a crucial role in the spread of these viruses and may provide a target for antiviral therapies.…”