Non-covalent binding of membrane lipids to membrane proteins

Polar lipids and membrane proteins are major components of biological membranes, both cell membranes and membranes of enveloped viruses. How these two classes of membrane components interact with each other to influence the function of biological membranes is a fundamental question that has attracted intense interest since the origins of the field of membrane studies. One of the most powerful ideas that driven the field is the likelihood that lipids bind to membrane proteins at specific sites, modulating protein structure and function. However only relatively recently has high resolution structure determination of membrane proteins progressed to the point of providing atomic level structure of lipid binding sites on membrane proteins. Analysis of X-ray diffraction, electron crystallography and NMR data over 100 specific lipid binding sites on membrane proteins. These data demonstrate tight lipid binding of both phospholipids and cholesterol to membrane proteins. Membrane lipids bind to membrane proteins by their headgroups, or by their acyl chains, or binding is mediated by the entire lipid molecule. When headgroups bind, binding is stabilized by polar interactions between lipid headgroups and the protein. When acyl chains bind, van der Waals effects dominate as the acyl chains adopt conformations that complement particular sites on the rough protein surface. No generally applicable motifs for binding have yet emerged. Previously published biochemical and biophysical data link this binding with function. This Article is Part of a Special Issue Entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy.     

Recent developments in membrane-protein structural genomics

Recent work has identified the topology of almost all the inner membrane proteins in Escherichia coli, and advances in nuclear magnetic resonance spectroscopy now allow the determination of α-helical membrane protein structures at high resolution. Together these developments will help overcome the current limitations of high-throughput determination of membrane protein structures.     

A conceptual model of organo-mineral interactions in soils: self-assembly of organic molecular fragments into zonal structures on mineral surfaces

In this paper, we propose a structure for organo-mineral associations in soils based on recent insights concerning the molecular structure of soil organic matter (SOM), and on extensive published evidence from empirical studies of organo-mineral interfaces. Our conceptual model assumes that SOM consists of a heterogeneous mixture of compounds that display a range of amphiphilic or surfactant-like properties, and are capable of self-organization in aqueous solution. An extension of this self-organizational behavior in solution, we suggest that SOM sorbs to mineral surfaces in a discrete zonal sequence. In the contact zone, the formation of particularly strong organo-mineral associations appears to be favored by situations where either (i) polar organic functional groups of amphiphiles interact via ligand exchange with singly coordinated mineral hydroxyls, forming stable inner-sphere complexes, or (ii) proteinaceous materials unfold upon adsorption, thus increasing adhesive strength by adding hydrophobic interactions to electrostatic binding. Entropic considerations dictate that exposed hydrophobic portions of amphiphilic molecules adsorbed directly to mineral surfaces be shielded from the polar aqueous phase through association with hydrophobic moieties of other amphiphilic molecules. This process can create a membrane-like bilayer containing a hydrophobic zone, whose components may exchange more easily with the surrounding soil solution than those in the contact zone, but which are still retained with considerable force. Sorbed to the hydrophilic exterior of hemimicellar coatings, or to adsorbed proteins, are organic molecules forming an outer region, or kinetic zone, that is loosely retained by cation bridging, hydrogen bonding, and other interactions. Organic material in the kinetic zone may experience high exchange rates with the surrounding soil solution, leading to short residence times for individual molecular fragments. The thickness of this outer region would depend more on input than on the availability of binding sites, and would largely be controlled by exchange kinetics. Movement of organics into and out of this outer region can thus be viewed as similar to a phase-partitioning process. The zonal concept of organo-mineral interactions presented here offers a new basis for understanding and predicting the retention of organic compounds, including contaminants, in soils and sediments.     

Surface-layer protein extracts from Lactobacillus helveticus inhibit enterohaemorrhagic Escherichia coli O157:H7 adhesion to epithelial cells

Adherence of intestinal pathogens, including Escherichia coli O157:H7, to human intestinal epithelial cells is a key step in pathogenesis. Probiotic bacteria, including Lactobacillus helveticus R0052 inhibit the adhesion of E. coli O157:H7 to epithelial cells, a process which may be related to specific components of the bacterial surface. Surface-layer proteins (Slps) are located in a paracrystalline layer outside the bacterial cell wall and are thought to play a role in tissue adherence. However, the ability of S-layer protein extract derived from probiotic bacteria to block adherence of enteric pathogens has not been investigated. Human epithelial (HEp-2 and T84) cells were treated with S-layer protein extract alone, infected with E. coli O157:H7, or pretreated with S-layer protein extract prior to infection to determine their importance in the inhibition of pathogen adherence. The effects of S-layer protein extracts were characterized by phase-contrast and immunofluorescence microscopy and measurement of the transepithelial electrical resistance of polarized monolayers. Pre-treatment of host epithelial cells with S-layer protein extracts prior to E. coli O157:H7 infection decreased pathogen adherence and attaching-effacing lesions in addition to preserving the barrier function of monolayers. These in vitro studies indicate that a non-viable constituent derived from a probiotic strain may prove effective in interrupting the infectious process of an intestinal pathogen.     

Anadromy,potamodromy and residency in brown trout Salmo trutta: the role of genes and the environment

Brown trout Salmo trutta is endemic to Europe, western Asia and north-western Africa; it is a prominent member of freshwater and coastal marine fish faunas. The species shows two resident (river-resident, lake-resident) and three main facultative migratory life histories (downstream–upstream within a river system, fluvial–adfluvial potamodromous; to and from a lake, lacustrine–adfluvial (inlet) or allacustrine (outlet) potamodromous; to and from the sea, anadromous). River-residency v. migration is a balance between enhanced feeding and thus growth advantages of migration to a particular habitat v. the costs of potentially greater mortality and energy expenditure. Fluvial–adfluvial migration usually has less feeding improvement, but less mortality risk, than lacustrine–adfluvial or allacustrine and anadromous, but the latter vary among catchments as to which is favoured. Indirect evidence suggests that around 50% of the variability in S. trutta migration v. residency, among individuals within a population, is due to genetic variance. This dichotomous decision can best be explained by the threshold-trait model of quantitative genetics. Thus, an individual's physiological condition (e.g., energy status) as regulated by environmental factors, genes and non-genetic parental effects, acts as the cue. The magnitude of this cue relative to a genetically predetermined individual threshold, governs whether it will migrate or sexually mature as a river-resident. This decision threshold occurs early in life and, if the choice is to migrate, a second threshold probably follows determining the age and timing of migration. Migration destination (mainstem river, lake, or sea) also appears to be genetically programmed. Decisions to migrate and ultimate destination result in a number of subsequent consequential changes such as parr–smolt transformation, sexual maturity and return migration. Strong associations with one or a few genes have been found for most aspects of the migratory syndrome and indirect evidence supports genetic involvement in all parts. Thus, migratory and resident life histories potentially evolve as a result of natural and anthropogenic environmental changes, which alter relative survival and reproduction. Knowledge of genetic determinants of the various components of migration in S. trutta lags substantially behind that of Oncorhynchus mykiss and other salmonines. Identification of genetic markers linked to migration components and especially to the migration–residency decision, is a prerequisite for facilitating detailed empirical studies. In order to predict effectively, through modelling, the effects of environmental changes, quantification of the relative fitness of different migratory traits and of their heritabilities, across a range of environmental conditions, is also urgently required in the face of the increasing pace of such changes.     

Time to Stop Telling Biophysics Students that Light Is Primarily a Wave

Standard pedagogy introduces optics as though it were a consequence of Maxwell’s equations and only grudgingly admits, usually in a rushed aside, that light has a particulate character that can somehow be reconciled with the wave picture. Recent revolutionary advances in optical imaging, however, make this approach more and more unhelpful: How are we to describe two-photon imaging, FRET, localization microscopy, and a host of related techniques to students who think of light primarily as a wave? I was surprised to find that everything I wanted my biophysics students to know about light, including image formation, x-ray diffraction, and even Bessel beams, could be expressed as well (or better) from the quantum viewpoint pioneered by Richard Feynman. Even my undergraduate students grasp this viewpoint as well as (or better than) the traditional one, and by mid-semester they are already well positioned to integrate the latest advances into their understanding. Moreover, I have found that this approach clarifies my own understanding of new techniques.     

β-Amyloid-Induced Endothelial Necrosis and Inhibition of Nitric Oxide Production

Deposits of amyloid β-peptide (Aβ) in senile plaques and cerebral blood vessels is the prominent feature of Alzheimer's disease (AD), regardless of genetic predisposition. The cellular origin of cerebral deposits of Aβ or its precise role in the neurodegenerative process has not been established. Recently we demonstrated a novel action of β-amyloid on blood vessels—vasoactivity and endothelial damage through superoxide radicals. Since endothelial dysfunction is associated with vascular degenerative diseases, we examined the direct action of Aβ on endothelial cells in culture. Cells treated with Aβ displayed characteristics of necrotic cell death which was prevented by the free radical scavenging enzyme superoxide dismutase. Stimulation of endothelial nitric oxide (NO) production by the calcium ionophore, A23187, or bradykinin was inhibited by β-amyloid. We conclude that an imbalance of NO and oxygen radicals may mediate the Aβ-induced endothelial damage on endothelial cells in culture and may also contribute to a variety of pathophysiological conditions associated with aging: hypertension, cerebral ischemia, vasospasm, or stroke.     

Targeting the apoptosis pathway to treat tumours of the paediatric nervous system

New, more effective therapeutics are required for the treatment of paediatric cancers. Current treatment protocols of cytotoxic treatments including chemotherapy trigger cancer-cell death by engaging the apoptosis pathway, and chemotherapy efficacy is frequently impeded by apoptosis dysregulation. Apoptosis dysregulation, through genetic or epigenetic mechanisms, is a feature of many cancer types, and contributes to reduced treatment response, disease progression and ultimately treatment resistance. Novel approaches are required to overcome dysregulated apoptosis signalling, increase the efficacy of cancer treatment and improve patient outcomes. Here, we provide an insight into current knowledge of how the apoptosis pathway is dysregulated in paediatric nervous system tumours, with a focus on TRAIL receptors, the BCL-2 proteins and the IAP family, and highlight preclinical evidence demonstrating that pharmacological manipulation of the apoptosis pathway can restore apoptosis signalling and sensitise cancer cells to treatment. Finally, we discuss the potential clinical implications of these findings.Subject terms: Cancer therapeutic resistance, Paediatric cancer, CNS cancer, Chemotherapy