146 research outputs found
Cholesterol-Induced Protein Sorting: An Analysis of Energetic Feasibility
AbstractThe mechanism(s) underlying the sorting of integral membrane proteins between the Golgi complex and the plasma membrane remain uncertain because no specific Golgi retention signal has been found. Moreover one can alter a protein's eventual localization simply by altering the length of its transmembrane domain (TMD). M. S. Bretscher and S. Munro (Science. 261:1280â1281, 1993) therefore proposed a physical sorting mechanism based on the hydrophobic match between the proteinsâ TMD and the bilayer thickness, in which cholesterol would regulate protein sorting by increasing the lipid bilayer thickness. In this model, Golgi proteins with short TMDs would be excluded from cholesterol-enriched domains (lipid rafts) that are incorporated into transport vesicles destined for the plasma membrane. Although attractive, this model remains unproven. We therefore evaluated the energetic feasibility of a cholesterol-dependent sorting process using the theory of elastic liquid crystal deformations. We show that the distribution of proteins between cholesterol-enriched and cholesterol-poor bilayer domains can be regulated by cholesterol-induced changes in the bilayer physical properties. Changes in bilayer thickness per se, however, have only a modest effect on sorting; the major effect arises because cholesterol changes also the bilayer material properties, which augments the energetic penalty for incorporating short TMDs into cholesterol-enriched domains. We conclude that cholesterol-induced changes in the bilayer physical properties allow for effective and accurate sorting which will be important generally for protein partitioning between different membrane domains
Investigation of the effect of UV-LED exposure conditions on the production of vitamin D in pig skin
Membrane-protein interactions in mechanosensitive channels
In this paper, we examine the mechanical role of the lipid bilayer in ion
channel conformation and function with specific reference to the case of the
mechanosensitive channel of large conductance (MscL). In a recent paper
(Wiggins and Phillips, 2004), we argued that mechanotransduction very naturally
arises from lipid-protein interactions by invoking a simple analytic model of
the MscL channel and the surrounding lipid bilayer. In this paper, we focus on
improving and expanding this analytic framework for studying lipid-protein
interactions with special attention to MscL. Our goal is to generate simple
scaling relations which can be used to provide qualitative understanding of the
role of membrane mechanics in protein function and to quantitatively interpret
experimental results. For the MscL channel, we find that the free energies
induced by lipid-protein interaction are of the same order as the free energy
differences between conductance states measured by Sukharev et al. (1999). We
therefore conclude that the mechanics of the bilayer plays an essential role in
determining the conformation and function of the channel. Finally, we compare
the predictions of our model to experimental results from the recent
investigations of the MscL channel by Perozo et al. (2002), Powl et al. (2003),
Yoshimura et al. (2004), and others and suggest a suite of new experiments
Thiazolidinedione insulin sensitizers alter lipid bilayer properties and voltage-dependent sodium channel function: implications for drug discovery
The thiazolidinediones (TZDs) are used in the treatment of diabetes mellitus type 2. Their canonical effects are mediated by activation of the peroxisome proliferatorâactivated receptor Îł (PPARÎł) transcription factor. In addition to effects mediated by gene activation, the TZDs cause acute, transcription-independent changes in various membrane transport processes, including glucose transport, and they alter the function of a diverse group of membrane proteins, including ion channels. The basis for these off-target effects is unknown, but the TZDs are hydrophobic/amphiphilic and adsorb to the bilayerâwater interface, which will alter bilayer properties, meaning that the TZDs may alter membrane protein function by bilayer-mediated mechanisms. We therefore explored whether the TZDs alter lipid bilayer properties sufficiently to be sensed by bilayer-spanning proteins, using gramicidin A (gA) channels as probes. The TZDs altered bilayer elastic properties with potencies that did not correlate with their affinity for PPARÎł. At concentrations where they altered gA channel function, they also altered the function of voltage-dependent sodium channels, producing a prepulse-dependent current inhibition and hyperpolarizing shift in the steady-state inactivation curve. The shifts in the inactivation curve produced by the TZDs and other amphiphiles can be superimposed by plotting them as a function of the changes in gA channel lifetimes. The TZDsâ partition coefficients into lipid bilayers were measured using isothermal titration calorimetry. The most potent bilayer modifier, troglitazone, alters bilayer properties at clinically relevant free concentrations; the least potent bilayer modifiers, pioglitazone and rosiglitazone, do not. Unlike other TZDs tested, ciglitazone behaves like a hydrophobic anion and alters the gA monomerâdimer equilibrium by more than one mechanism. Our results provide a possible mechanism for some off-target effects of an important group of drugs, and underscore the importance of exploring bilayer effects of candidate drugs early in drug development
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