An official website of the United States government
The Prion protein is the molecular hallmark of the incurable prion diseases affecting mammals, including humans. The protein-only hypothesis states that the misfolding, accumulation, and deposition of the Prion protein play a critical role in toxicity. The cellular Prion protein (PrPC) anchors to the extracellular leaflet of the plasma membrane and prefers cholesterol- and sphingomyelin-rich membrane domains. Conformational Prion protein conversion into the pathological isoform happens on the cell surface.In vitroandin vivoexperiments indicate that Prion protein misfolding, aggregation, and toxicity are sensitive to the lipid composition of plasma membranes and vesicles. A picture of the underlying biophysical driving forces that explain the effect of Prion protein - lipid interactions in physiological conditions is needed to develop a structural model of Prion protein conformational conversion. To this end, we use molecular dynamics simulations that mimic the interactions between the globular domain of PrPCanchored to model membrane patches. In addition, we also simulate the Doppel protein anchored to such membrane patches. The Doppel protein is the closest in the phylogenetic tree to PrPC, localizes in an extracellular milieu similar to that of PrPC, and exhibits a similar topology to PrPCeven if the amino acid sequence is only 25% identical. Our simulations show that specific protein-lipid interactions and conformational constraints imposed by GPI anchoring together favor specific binding sites in globular PrPCbut not in Doppel. Interestingly, the binding sites we found in PrPCcorrespond to prion protein loops, which are critical in aggregation and prion disease transmission barrier (β2-α2 loop) and in initial spontaneous misfolding (α2-α3 loop). We also found that the membrane re-arranges locally to accommodate protein residues inserted in the membrane surface as a response to protein binding.
more »
« less
Track: High Throughput Protein Science Thermal and mechanical stability of highly-luminescent protein NanoLuc in presence and absence of chaperones; Award Winners/Abstracts from the 36th Annual Symposium of The Protein Society, July 7 – 10, 2022
More Like this
-
-
The effects of detergent sodium dodecyl sulfate (SDS) on protein structure and dynamics are fundamental to the most common laboratory technique used to separate proteins and determine their molecular weights: polyacrylamide gel electrophoresis. However, the mechanism by which SDS induces protein unfolding and the microstructure of protein–SDS complexes remain largely unknown. Here, we report a detailed account of SDS-induced unfolding of two proteins—I27 domain of titin and β-amylase—obtained through all-atom molecular dynamics simulations. Both proteins were found to spontaneously unfold in the presence of SDS at boiling water temperature on the time scale of several microseconds. The protein unfolding was found to occur via two distinct mechanisms in which specific interactions of individual SDS molecules disrupt the protein's secondary structure. In the final state of the unfolding process, the proteins are found to wrap around SDS micelles in a fluid necklace-and-beads configuration, where the number and location of bound micelles changes dynamically. The global conformation of the protein was found to correlate with the number of SDS micelles bound to it, whereas the number of SDS molecules directly bound to the protein was found to define the relaxation time scale of the unfolded protein. Our microscopic characterization of SDS–protein interactions sets the stage for future refinement of SDS–enabled protein characterization methods, including protein fingerprinting and sequencing using a solid-state nanopore.more » « less
-
Summary The evolutionary modification of development was fundamental in generating extant plant diversity. Similarly, the modification of development is a path forward to engineering the plants of the future, provided we know enough about what to modify. Understanding how extant diversity was generated will reveal productive pathways forward for modifying development. Here, I discuss four examples of developmental pathways that have been remodeled by changes to protein–protein interactions. These are cases where changes to developmental pathways have been paralleled by recent changes, selected for or engineered by humans. Extant plant diversity represents a vast treasure trove of molecular solutions to ecological problems. Mining this treasure trove will allow for the intentional modification of plant development for solving future problems.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1002/pro.4494
