Biology subjects

Draganova, E. B.

Publications and source records attributed to Draganova, E. B..

3 recordsLinked to original sources

bioRxiv2023

The universal suppressor mutation in the HSV-1 nuclear egress complex restores membrane budding defects by stabilizing the oligomeric lattice

Nuclear egress is an essential process in herpesviral replication whereby nascent capsids translocate from the nucleus to the cytoplasm. This initial step of nuclear egress - budding at the inner nuclear membrane - is coordinated by the nuclear egress complex (NEC). Composed of the viral proteins UL31 and UL34, NEC deforms the membrane around the capsid as the latter buds into the perinuclear space. NEC oligomerization into a hexagonal membrane-bound lattice is essential for budding because mutations designed to perturb lattice interfaces reduce its budding ability. Previously, we identified an NEC suppressor mutation capable of restoring budding to a mutant with a weakened hexagonal lattice. Here, we show that the suppressor mutation can restore budding to a broad range of budding-deficient NEC mutants thereby acting as a universal suppressor. We demonstrate that the suppressor mutation indirectly promotes the formation of new contacts between the NEC hexamers that, ostensibly, stabilize the hexagonal lattice. This stabilization strategy is powerful enough to override the otherwise deleterious effects of mutations that destabilize the NEC lattice by different mechanisms, resulting in a functional NEC hexagonal lattice and restoration of membrane budding.

biophysics↗

bioRxiv2020

Virally derived peptide inhibitors of the herpes simplex virus type 1 nuclear egress complex

Herpesviruses infect a majority of the human population, establishing lifelong latent infections for which there is no cure. Periodic viral reactivation spreads infection to new hosts while causing various disease states particularly detrimental in the immunocompromised. Efficient viral replication, and ultimately the spread of infection, is dependent on the nuclear egress complex (NEC), a conserved viral heterodimer that helps translocate mature viral capsids from the nucleus to the cytoplasm where they mature into infectious virions. Here, we have identified peptides capable of inhibiting the membrane-budding activity of the NEC in vitro. Biophysical characterization of these peptides using circular dichroism suggests that secondary structure, rather than amino acid sequence, influences the extent of inhibition. Current therapeutics that target viral DNA replication machinery are rendered ineffective by drug resistance due to viral mutations. Our results establish a basis for the development of an alternative class of inhibitors against nuclear egress, an essential step in herpesvirus replication, potentially expanding the current repertoire of available therapeutics.

microbiology↗

bioRxiv2020

Structural basis for capsid recruitment and coat formation during HSV-1 nuclear egress

During herpesvirus infection, egress of nascent viral capsids from the nucleus is mediated by the viral nuclear egress complex (NEC). NEC deforms the inner nuclear membrane (INM) around the capsid by forming a hexagonal array. However, how the NEC coat interacts with the capsid and how curved coats are generated to enable budding is yet unclear. Here, by structure-guided truncations, confocal microscopy, and cryoelectron tomography, we show that binding of the capsid protein UL25 promotes the formation of NEC pentagons rather than hexagons. We hypothesize that during nuclear budding, binding of UL25 situated at the pentagonal capsid vertices to the NEC at the INM promotes formation of NEC pentagons that would anchor the NEC coat to the capsid. Incorporation of NEC pentagons at the points of contact with the vertices would also promote assembly of the curved hexagonal NEC coat around the capsid, leading to productive egress of UL25-decorated capsids.

microbiology↗