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Synthetic cell membranes invented at the Institute of Materials Research and Engineering (IMRE), a research institute of Singapore’s Agency for Science, Technology and Research (A*STAR), may improve the way we identify and develop drugs by speeding up and reducing the cost of the drug screening process. The technology earned a spot as one of the twelve finalists in the Asian Innovation Awards 2011 organized by the Wall Street Journal Asia. See the original post: Proteins (2011), pp. n/a-n/a. Abstract Large-scale next generation resequencing of X chromosome genes identified a missense mutation in the CLIC2 gene on Xq28 in a male with X-linked intellectual disability (XLID) and not found in healthy individuals. At the same time, numerous nsSNPs (nonsynonomous SNP) have been reported in the CLIC2 gene in healthy individuals indicating that the CLIC2 protein can tolerate amino acid substitutions and be fully functional. To test the possibility that p.H101Q is a disease-causing mutation, we performed in silico simulations to calculate the effects of the p.H101Q mutation on CLIC2 stability, dynamics and ionization states while comparing the effects obtained for presumably harmless nsSNPs. It was found that p.H101Q, in contrast with other nsSNPs, (a) lessens the flexibility of the joint loop which is important for the normal function of CLIC2, (b) makes the overall 3D structure of CLIC2 more stable and thus reduces the possibility of the large conformational change expected to occur when CLIC2 moves from a soluble to membrane form and (c) removes the positively charged residue, H101, which may be important for the membrane association of CLIC2. The results of in silico modeling, in conjunction with the polymorphism analysis, suggest that p.H101Q may be a disease-causing mutation, the first one suggested in the CLIC family. Proteins 2011. © 2011 Wiley-Liss, Inc. The Journal of Physical Chemistry B, Vol. 115, No. 19. (19 May 2011), pp. 5693-5706. Dynamics of confined water has interesting implications in the organization and function of molecular assemblies such as membranes. A direct consequence of this type of organization is the restriction imposed on the mobility of the constituent structural units. Interestingly, this restriction (confinement) of mobility couples the motion of solvent (water) molecules with the slow moving molecules in the assembly. It is in this context that the red edge excitation shift (REES) represents a sensitive approach to monitor the environment and dynamics around a fluorophore in such organized assemblies. A shift in the wavelength of maximum fluorescence emission toward higher wavelengths, caused by a shift in the excitation wavelength toward the red edge of the absorption band, is termed REES. REES relies on slow solvent reorientation in the excited state of a fluorophore that can be used to monitor the environment and dynamics around a fluorophore in a host assembly. In this article, we focus on the application of REES to monitor organization and dynamics of membrane probes and proteins. Link: %content% View original post here: %content% See the article here: %content% Read more from the original source: %content% Go here to read the rest: %content% Go here to see the original: %content% See the rest here: Methods in molecular biology (Clifton, N.J.) In Molecular Modeling of Proteins, Vol. 443 (2008), pp. 147-160. Membrane protein structures are underrepresented in the Protein Data Bank (PDB) because of difficulties associated with expression and crystallization. As such, it is one area in which computational studies, particularly molecular dynamics (MD), can provide useful additional information. Recently, there has been substantial progress in the simulation of lipid bilayers and membrane proteins embedded within them. Initial efforts at simulating membrane proteins embedded within a lipid bilayer were relatively slow and interactive processes, but recent advances now mean that the setup and running of membrane protein simulations is somewhat more straightforward, although not without its problems. In this chapter, we outline practical methods for setting up and running MD simulations of a membrane protein embedded within a lipid bilayer and discuss methodologies that are likely to contribute future improvements. Researchers have developed new nanotechnologies for wound healing and blood-vessel tissue, and have determined how ribosomes insert a growing protein into a cellular membrane. Read this article: %content% See the article here: In Proteins Membrane Binding and Pore Formation, Vol. 677 (2010), pp. 31-55. Bilayer lipids, far from being passive elements, have multiple roles in polypeptide-dependent pore formation. Lipids participate at all stages of the formation of pores by providing the binding site for proteins and peptides, conditioning their active structure and modulating the molecular reorganization of the membrane complex. Such general functions of lipids superimpose to other particular roles, from electrostatic and curvature effects to more specific actions in cases like cholesterol, sphingolipids or cardiolipin. Pores are natural phenomena in lipid membranes. Driven by membrane fluctuations and packing defects, transient water pores are related to spontaneous lipid flip-flop and non-assisted ion permeation. In the absence of proteins or peptides, these are rare short living events, with properties dependent on the lipid composition of the membrane. Their frequency increases under conditions of internal membrane disturbance of the lipid packing, like in the presence of membrane-bound proteins or peptides. These latter molecules, in fact, form dynamic supramolecular assemblies together with the lipids and transmembrane pores are one of the possible structures of the complex. Active peptides and proteins can thus be considered inducers or enhancers of pores which increase their probability and lifetime by modifying the thermodynamic membrane balance. This includes destabilizing the membrane lamellar structure, lowering the activation energy for pore formation and stabilizing the open pore structure. Link: Mol Membr Biol In Molecular Membrane Biology, Vol. 26, No. 1-2. (1 January 2009), pp. 55-66. S-Palmitoylation is a reversible post-translational modification that results in the addition of a C16-carbon saturated fatty acyl chain to cytoplasmic cysteine residues. This modification is mediated by Palmitoyl-acyl Transferases that are starting to be investigated, and reversed by Protein Palmitoyl Thioesterases, which remain enigmatic. Palmitoylation of cytoplasmic proteins has been well described to regulate the interaction of these soluble proteins with specific membranes or membrane domains. Less is known about the consequences of palmitoylation in transmembrane proteins not only due to the dual difficulty of following a lipid modification and dealing with membrane proteins, but also due to the complexity of the palmitoylation-induced behavior. Moreover, possibly because the available data set is limited, the change in behavior induced by palmitoylation of a transmembrane protein is currently not predictable. We here review the various consequences reported for the palmitoylation of membrane proteins, which include improper folding in the endoplasmic reticulum, retention in the Golgi, inability to assemble into protein platforms, altered signaling capacity, premature endocytosis and missorting in the endocytic pathway. We then discuss the possible underlying mechanisms, in particular the ability of palmitoylation to control the conformation of transmembrane segments, to modify the affinity of a membrane protein for specific membrane domains and to control protein-protein interactions. S-Palmitoylation is a reversible post-translational modification that results in the addition of a C16-carbon saturated fatty acyl chain to cytoplasmic cysteine residues. This modification is mediated by Palmitoyl-acyl Transferases that are starting to be investigated, and reversed by Protein Palmitoyl Thioesterases, which remain enigmatic. Palmitoylation of cytoplasmic proteins has been well described to regulate the interaction of these soluble proteins with specific membranes or membrane domains. Less is known about the consequences of palmitoylation in transmembrane proteins not only due to the dual difficulty of following a lipid modification and dealing with membrane proteins, but also due to the complexity of the palmitoylation-induced behavior. Moreover, possibly because the available data set is limited, the change in behavior induced by palmitoylation of a transmembrane protein is currently not predictable. We here review the various consequences reported for the palmitoylation of membrane proteins, which include improper folding in the endoplasmic reticulum, retention in the Golgi, inability to assemble into protein platforms, altered signaling capacity, premature endocytosis and missorting in the endocytic pathway. We then discuss the possible underlying mechanisms, in particular the ability of palmitoylation to control the conformation of transmembrane segments, to modify the affinity of a membrane protein for specific membrane domains and to control protein-protein interactions. Proteins, Vol. 78, No. 14. (2010), pp. 2895-2907. Abstract The evolution of protein folds is under strong constraints from their surrounding environment. Although folding in water-soluble proteins is driven primarily by hydrophobic forces, the nature of the forces that determine the folding and stability of transmembrane proteins are still not fully understood. Furthermore, the chemically heterogeneous lipid bilayer has a non-uniform effect on protein structure. In this article, we attempt to get an insight into the nature of this effect by examining the impact of various types of local structure environment on amino acid substitution, based on alignments of high-resolution structures of polytopic helical transmembrane proteins combined with sequences of close homologs. Compared to globular proteins, burying amino acid sidechains, especially hydrophilic ones, led to a lower increase in conservation in both the lipid-water interface region and the hydrocarbon core region. This observation is due to surface residues in HTM proteins especially in the HC region being relatively highly conserved, suggesting higher evolutionary constraints from their specific interactions with the surrounding lipid molecules. Polar and small residues, particularly Pro and Gly, show a noticeable increase in conservation as they are positioned more towards the centre of the membrane, which is consistent with their recognized key roles in structural stability. In addition, the examination of hydrogen bonds in the membrane environment identified some exposed hydrophilic residues being better conserved when not hydrogen-bonded to other residues, supporting the importance of lipid-protein sidechain interactions. The conclusions presented in this study highlight the distinct features of substitution matrices that take into account the membrane environment, and their potential role in improving sequence-structure alignments of transmembrane proteins. Proteins 2010; © 2010 Wiley-Liss, Inc. Link: |
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