Biology subjects

Straub, J. E.

Publications and source records attributed to Straub, J. E..

3 recordsLinked to original sources

bioRxiv2018

Regimes of Complex Lipid Bilayer Phases Induced by Cholesterol Concentration in MD Simulation.

Cholesterol is essential to the formation of phase separated lipid domains in membranes. Lipid domains can exist in different thermodynamic phases depending on the molecular composition, and play significant roles in determining structure and function of membrane proteins. We investigate the role of cholesterol in the structure and dynamics of ternary lipid mixtures displaying phase separation using Molecular Dynamics simulations, employing a physiologically-relevant span of cholesterol concentration. We find that cholesterol can induce formation of three regimes of phase behavior, I) miscible liquid disordered bulk, II) phase separated, domain registered coexistence of liquid disordered and liquid ordered and domains, and III) phase separated, domain-anti-registered coexistence of liquid-disordered and newly-identified nanoscopic gel domains composed of cholesterol threads we name \"cholesterolic gel\" domains. These findings are validated and discussed in the context of current experimental knowledge, models of cholesterol spatial distributions, and models of ternary lipid mixture phase separation.

biophysics↗

bioRxiv2018

Sequence effects on size, shape, and structural heterogeneity in Intrinsically Disordered Proteins

Intrinsically disordered proteins (IDPs) lack well-defined three-dimensional structures, thus challenging the archetypal notion of structure-function relationships. Determining the ensemble of conformations that IDPs explore under physiological conditions is the first step towards understanding their diverse cellular functions. Here, we quantitatively characterize the structural features of IDPs as a function of sequence and length using coarse-grained simulations. For diverse IDP sequences, with the number of residues (NT) ranging from 24 to 441, our simulations not only reproduce the radii of gyration (Rg) obtained from experiments, but also predict the full scattering intensity profiles in very good agreement with Small Angle X-ray Scattering experiments. The Rg values are well-described by the standard Flory scaling law, [Formula], with v {approx} 0.588, making it tempting to assert that IDPs behave as polymers in a good solvent. However, clustering analysis reveals that the menagerie of structures explored by IDPs is diverse, with the extent of heterogeneity being highly sequence-dependent, even though ensemble-averaged properties, such as the dependence of Rg on chain length, may suggest synthetic polymer-like behavior in a good solvent. For example, we show that for the highly charged Prothymosin-, a substantial fraction of conformations is highly compact. Even if the sequence compositions are similar, as is the case for -Synuclein and a truncated construct from the Tau protein, there are substantial differences in the conformational heterogeneity. Taken together, these observations imply that metrics based on net charge or related quantities alone, cannot be used to anticipate the phases of IDPs, either in isolation or in complex with partner IDPs or RNA. Our work sets the stage for probing the interactions of IDPs with each other, with folded protein domains, or with partner RNAs, which are critical for describing the structures of stress granules and biomolecular condensates with important cellular functions. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/427476v2_ufig1.gif" ALT="Figure 1"> View larger version (12K): org.highwire.dtl.DTLVardef@1b50bd9org.highwire.dtl.DTLVardef@11cf542org.highwire.dtl.DTLVardef@29ebb5org.highwire.dtl.DTLVardef@31e965_HPS_FORMAT_FIGEXP M_FIG Graphical TOC Entry C_FIG

biophysics↗

bioRxiv2018

Molecular basis for a novel systemic form of human hereditary apoA-I amyloidosis with vision loss

Hereditary apolipoprotein A-I (apoA-I) amyloidosis (AApoAI) is a life-threatening incurable genetic disorder whose molecular underpinnings and the full spectrum of afflicted organs are unclear. We report a new form of AApoAI with amyloid deposition in multiple organs, including an unprecedented retinal amyloidosis. Genetic and proteomic analyses identified Glu34Lys apoA-I as the fibrillar protein causing the clinical manifestations. A life-saving combined hepatorenal transplantation was performed for one Glu34Lys carrier. To elucidate structural underpinnings for amyloidogenic properties of Glu34Lys, we generated its recombinant globular domain and compared the conformation and dynamics of its lipid-free form with those of two other naturally occurring apoA-I variants, Phe71Tyr (amyloidogenic) and Leu159Arg (non-amyloidogenic). All variants showed reduced stability and altered aromatic residue packing. Molecular dynamics simulations revealed local helical unfolding and suggested that transient opening of Trp72 induced mutation-dependent structural perturbations in a sensitive region, including the major amyloid hotspot residues 14-22. We posit that a shift from the \"closed\" to an \"open\" orientation of Trp72 modulates structural protection of amyloid hotspots, suggesting a previously unknown early step in protein misfolding.

molecular biology↗