@article {31050, title = {Mechanism of aggregation and membrane interactions of mammalian prion protein.}, journal = {Biochim Biophys Acta}, year = {2018}, month = {2018 Mar 04}, abstract = {

The cellular prion protein (PrP), which is present ubiquitously in all mammalian neurons, is normally found to be linked to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. The conformational conversion of PrPinto misfolded and aggregated forms is associated with transmissible neurodegenerative diseases known as prion diseases. The importance of different misfolded conformations in prion diseases, and the mechanism by which prion aggregates induce neurotoxicity remain poorly understood. Multiple studies have been shown that the toxicity of misfolded prion protein is directly correlated with its ability to interact with and perturb membranes. This review describes the current progress toward understanding prion protein misfolding and aggregation, as well as the interaction of prion protein aggregates with lipid membrane.

}, issn = {0006-3002}, doi = {10.1016/j.bbamem.2018.02.031}, author = {Sabareesan, Ambadi Thody and Mathew, M K and Udgaonkar, Jayant B} } @article {28252, title = {The G126V Mutation in the Mouse Prion Protein Hinders Nucleation-Dependent Fibril Formation by Slowing Initial Fibril Growth and by Increasing the Critical Concentration.}, journal = {Biochemistry}, volume = {56}, year = {2017}, month = {2017 11 07}, pages = {5931-5942}, abstract = {

The middle disordered hydrophobic region of the prion protein plays a critical role in conformational conversion of the protein, with pathogenic as well as protective mutations being localized to this region. In particular, it has been shown that the G127V mutation in this region of the human prion protein (huPrP) is protective against the spread of prion disease, but the mechanism of protection remains unknown. In this study, quantitative analyses of the kinetics of fibril formation by wild-type mouse prion protein (moPrP) and G126V moPrP (equivalent to G127V huPrP) reveal important differences: the critical concentration is higher, the lag phase is longer, and the initial effective rate constant of fibril growth is slower for the mutant variant. The study offers a simple biophysical explanation for why the G127V mutation in huPrP would be protective in humans: the \~{}5-fold increase in critical concentration caused by the mutation likely results in the critical concentration (below which fibril formation cannot occur) being higher that the concentration of the protein present in and on cells in vivo.

}, keywords = {Animals, Humans, Hydrophobic and Hydrophilic Interactions, Kinetics, Mice, Models, Theoretical, Mutation, Missense, Polymerization, Prion Proteins, PrP 27-30 Protein}, issn = {1520-4995}, doi = {10.1021/acs.biochem.7b00894}, author = {Sabareesan, Ambadi Thody and Udgaonkar, Jayant B} } @article {3540, title = {The Pathogenic A116V Mutation Enhances Ion-Selective Channel Formation by Prion Protein in Membranes.}, journal = {Biophys J}, volume = {110}, year = {2016}, month = {2016 Apr 26}, pages = {1766-76}, abstract = {

Prion diseases are a group of fatal neurodegenerative disorders that afflict mammals. Misfolded and aggregated forms of the prion protein (PrP(Sc)) have been associated with many prion diseases. A transmembrane form of PrP favored by the pathogenic mutation A116V is associated with Gerstmann-Str{\"a}ussler-Scheinker syndrome, but no accumulation of PrP(Sc) is detected. However, the role of the transmembrane form of PrP in pathological processes leading to neuronal death remains unclear. This study reports that the full-length mouse PrP (moPrP) significantly increases the permeability of living cells to K(+), and forms K(+)- and Ca(2+)-selective channels in lipid membranes. Importantly, the pathogenic mutation A116V greatly increases the channel-forming capability of moPrP. The channels thus formed are impermeable to sodium and chloride ions, and are blocked by blockers of voltage-gated ion channels. Hydrogen-deuterium exchange studies coupled with mass spectrometry (HDX-MS) show that upon interaction with lipid, the central hydrophobic region (109-132) of the protein is protected against exchange, making it a good candidate for inserting into the membrane and lining the channel. HDX-MS also shows a dramatic increase in the protein-lipid stoichiometry for A116V moPrP, providing a rationale for its increased channel-forming capability. The results suggest that ion channel formation may be a possible mechanism of PrP-mediated neurodegeneration by the transmembrane forms of PrP.

}, issn = {1542-0086}, doi = {10.1016/j.bpj.2016.03.017}, author = {Sabareesan, Ambadi Thody and Singh, Jogender and Roy, Samrat and Udgaonkar, Jayant B and Mathew, M K} }