Jamal, S. | bioRxiv Science

bioRxiv2023

Oligomeric states of an Influenza-encoded PB1-F2 viroporin

Influenza Viruses have always been a major health concern due to their highly contagious nature. The PB1-F2 viroporin encoded by the influenza A virus is known to be a pro-apoptotic protein involved in cell death induction of the host immune cells. The structural arrangement and the mode of action of PB1-F2 viroporin have not been fully understood. In this study, we report on the most probable oligomeric structural existences of PB1-F2, investigated by Molecular Dynamics Simulations with improved sampling of conformational states. The simulations provide a channel framework to study the mitochondrial membrane permeation pathway which could initiate the leakage of mitochondrial contents like cytochrome C and induce apoptosis. The structural attributes of the oligomeric states were rigorously evaluated by comparing the experimental reports. Our results reveal a tetrameric form as the preferable state in the lipid environment. This further fulfills the ion transportation criteria by providing a less energetic barrier to ions/water molecules crossing the membrane.

biophysics↗

bioRxiv2023

Selective endocytic uptake of targeted liposomes occurs within a narrow range of liposome diameter

Cell surface receptors facilitate signaling and nutrient uptake. These processes are dynamic, requiring receptors to be actively recycled by endocytosis. Due to their differential expression in disease states, receptors are often the target of drug-carrier particles, which are adorned with ligands that bind specifically to receptors. These targeted particles are taken into the cell by multiple routes of internalization, where the best-characterized pathway is clathrin-mediated endocytosis. Most studies of particle uptake have utilized bulk assays, rather than observing individual endocytic events. As a result, the detailed mechanisms of particle uptake remain obscure. To address this gap, we have employed a live-cell imaging approach to study the uptake of individual liposomes as they interact with clathrin-coated structures. By tracking individual internalization events, we find that the size of liposomes, rather than the density of the ligands on their surfaces, primarily determines their probability of uptake. Interestingly, targeting has the greatest impact on endocytosis of liposomes of intermediate diameters, with the smallest and largest liposomes being internalized or excluded, respectively, regardless of whether they are targeted. These findings, which highlight a previously unexplored limitation of targeted delivery, can be used to design more effective drug carriers.

bioengineering↗