Throughout the biological world, a 30 A hydrophobic film typically delimits the environments that serve as the margin between life and death for individual cells. Biochemical and biophysical findings have provided a detailed model of the composition and structure of membranes, which includes levels of dynamic organization both across the lipid bilayer (lipid asymmetry) and in the lateral dimension (lipid domains) of membranes. How do cells apply anabolic and catabolic enzymes, translocases and transporters, plus the intrinsic physical phase behaviour of lipids and their interactions with membrane proteins, to create the unique compositions and multiple functionalities of their individual membranes?

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Membrane lipids: where they are and how they behave.

Antimicrobial peptides are an abundant and diverse group of molecules that are produced by many tissues and cell types in a variety of invertebrate, plant and animal species. Their amino acid composition, amphipathicity, cationic charge and size allow them to attach to and insert into membrane bilayers to form pores by 'barrel-stave', 'carpet' or 'toroidal-pore' mechanisms. Although these models are helpful for defining mechanisms of antimicrobial peptide activity, their relevance to how peptides damage and kill microorganisms still need to be clarified. Recently, there has been speculation that transmembrane pore formation is not the only mechanism of microbial killing. In fact several observations suggest that translocated peptides can alter cytoplasmic membrane septum formation, inhibit cell-wall synthesis, inhibit nucleic-acid synthesis, inhibit protein synthesis or inhibit enzymatic activity. In this review the different models of antimicrobial-peptide-induced pore formation and cell killing are presented.

Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria?

T e purpose of this review is to assess the nature and magnitudes of the dominant forces in protein folding. Since proteins are only marginally stable at room temperature,’ no type of molecular interaction is unimportant, and even small interactions can contribute significantly (positively or negatively) to stability (Alber, 1989a,b; Matthews, 1987a,b). However, the present review aims to identify only the largest forces that lead to the structural features of globular proteins: their extraordinary compactness, their core of nonpolar residues, and their considerable amounts of internal architecture. This review explores contributions to the free energy of folding arising from electrostatics (classical charge repulsions and ion pairing), hydrogen-bonding and van der Waals interactions, intrinsic propensities, and hydrophobic interactions. An earlier review by Kauzmann (1959) introduced the importance of hydrophobic interactions. His insights were particularly remarkable considering that he did not have the benefit of known protein structures, model studies, high-resolution calorimetry, mutational methods, or force-field or statistical mechanical results. The present review aims to provide a reassessment of the factors important for folding in light of current knowledge. Also considered here are the opposing forces, conformational entropy and electrostatics. The process of protein folding has been known for about 60 years. In 1902, Emil Fischer and Franz Hofmeister independently concluded that proteins were chains of covalently linked amino acids (Haschemeyer & Haschemeyer, 1973) but deeper understanding of protein structure and conformational change was hindered because of the difficulty in finding conditions for solubilization. Chick and Martin (191 1) were the first to discover the process of denaturation and to distinguish it from the process of aggregation. By 1925, the denaturation process was considered to be either hydrolysis of the peptide bond (Wu & Wu, 1925; Anson & Mirsky, 1925) or dehydration of the protein (Robertson, 1918). The view that protein denaturation was an unfolding process was

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Dominant forces in protein folding

Prediction of protein conformation.

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Principles Of Fluorescence Spectroscopy

Molecular mechanisms of membrane targeting antibiotics

Huntington's disease is caused by an expanded polyglutamine tract in huntingtin protein, leading to accumulation of huntingtin in the nuclei of striatal neurons. The 18 amino-acid amino-terminus of huntingtin is an amphipathic alpha helical membrane-binding domain that can reversibly target to vesicles and the endoplasmic reticulum (ER). The association of huntingtin to the ER is affected by ER stress. A single point mutation in huntingtin 1-18 predicted to disrupt this helical structure displayed striking phenotypes of complete inhibition of polyglutamine-mediated aggregation, increased huntingtin nuclear accumulation and greatly increased mutant huntingtin toxicity in a striatal-derived mouse cell line. Huntingtin vesicular interaction mediated by 1-18 is specific to late endosomes and autophagic vesicles. We propose that huntingtin has a normal biological function as an ER-associated protein that can translocate to the nucleus and back out in response to ER stress or other events. The increased nuclear entry of mutant huntingtin due to loss of ER-targeting results in increased toxicity.

Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity

A method for facilitating the transfer of nucleic acids into cells comprising preparing a mixed lipid dispersion of a cationic lipid with a co-lipid in a suitable carrier solvent. The lipid has a structure which includes a lipophilic group derived from cholesterol, a linker bond, a spacer arm including from about 1 to about 20 carbon atoms in a branched or unbranched linear alkyl chain, and a cationic amino group selected from the group consisting of primary, secondary, tertiary and quaternary amino groups. The method further comprises adding the nucleic acids to the dispersion to form a complex. The cells are then treated with the complex. There is also disclosed a novel cationic amphiphile useful for this purpose.

Method for delivering nucleic acids into cells

Lipid polymorphism and protein-lipid interactions.

The iron-binding protein lactoferrin is a multifunctional protein that has antibacterial, antifungal, antiviral, antitumour, anti-inflammatory, and immunoregulatory properties. All of these additional properties appear to be related to its highly basic N-terminal region. This part of the protein can be released in the stomach by pepsin cleavage at acid pH. The 25-residue antimicrobial peptide that is released is called lactoferricin. In this work, we review our knowledge about the structure of the peptide and attempt to relate this to its many functions. Microcalorimetry and fluorescence spectroscopy data regarding the interaction of the peptide with model membranes show that binding to net negatively charged bacterial and cancer cell membranes is preferred over neutral eukaryotic membranes. Binding of the peptide destabilizes the regular membrane bilayer structure. Residues that are of particular importance for the activity of lactoferricin are tryptophan and arginine. These two amino acids are also prev...

Richard M. Epand

Papers

Molecular mechanisms of membrane targeting antibiotics

Huntingtin has a membrane association signal that can modulate huntingtin aggregation, nuclear entry and toxicity

Method for delivering nucleic acids into cells

Lipid polymorphism and protein-lipid interactions.

Towards a structure-function analysis of bovine lactoferricin and related tryptophan- and arginine-containing peptides.