ABSTRACT
The mitochondrial ADP/ATP carrier imports ADP from the cytosol and exports ATP from the mitochondrial matrix, which are key transport steps for oxidative phosphorylation in eukaryotic organisms. The transport protein belongs to the mitochondrial carrier family, a large transporter family in the inner membrane of mitochondria. It is one of the best studied members of the family and serves as a paradigm for the molecular mechanism of mitochondrial carriers. Structurally, the carrier consists of three homologous domains, each composed of two transmembrane α-helices linked with a loop and short α-helix on the matrix side. The transporter cycles between a cytoplasmic and matrix state in which a central substrate binding site is alternately accessible to these compartments for binding of ADP or ATP. On both the cytoplasmic and matrix side of the carrier are networks consisting of three salt bridges each. In the cytoplasmic state, the matrix salt bridge network is formed and the cytoplasmic network is disrupted, opening the central substrate binding site to the intermembrane space and cytosol, whereas the converse occurs in the matrix state. In the transport cycle, tighter substrate binding in the intermediate states allows the interconversion of conformations by lowering the energy barrier for disruption and formation of these networks, opening and closing the carrier to either side of the membrane in an alternating way. Conversion between cytoplasmic and matrix states might require the simultaneous rotation of three domains around a central translocation pathway, constituting a unique mechanism among transport proteins. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.
Subject(s)
Adenosine Diphosphate/metabolism , Adenosine Triphosphate/metabolism , Mitochondrial ADP, ATP Translocases/metabolism , Mitochondrial Membranes/metabolism , Amino Acid Sequence , Animals , Biological Transport, Active , Bongkrekic Acid/pharmacology , Cardiolipins/metabolism , Cattle , Consensus Sequence , Humans , Mitochondrial ADP, ATP Translocases/antagonists & inhibitors , Mitochondrial ADP, ATP Translocases/chemistry , Models, Molecular , Phosphate Transport Proteins/metabolism , Protein Conformation , Saccharomyces cerevisiae Proteins/chemistry , Saccharomyces cerevisiae Proteins/metabolism , Substrate SpecificityABSTRACT
Epidemiological evidence that red wine consumption negatively correlates with risk of Alzheimer's disease has led to experimental studies demonstrating that grape seed extracts inhibit the aggregation and oligomerization of Aß in vitro and ameliorate neuropathology and behavioral deficits in a mouse model of Alzheimer's disease. The active agent in the extracts is a mixed population of polyphenolic compounds. To evaluate the relative potency of each of these compounds, HPLC was used to fractionate the mixture into monomers, dimers, and oligomers. Each fraction was analyzed for its effect on Aß conformational dynamics (circular dichroism), oligomerization (zero-length photochemical cross-linking), aggregation kinetics (Thioflavin T fluorescence), and morphology (electron microscopy). The relative activities of each fraction were determined on the basis of molar concentration (mol/L) or mass concentration (g/L). When molar concentration, the number concentration of each polyphenolic compound, was considered, the oligomer fraction was the most potent inhibitor of Aß oligomerization and aggregation. However, when mass concentration, the number concentration of phenolic groups, was considered, monomers were the most potent inhibitors. To understand these ostensibly contradictory results, a model of polyphenol:Aß complexation was developed. This model, which was found to be consistent with published X-ray crystallographic studies, offers an explanation for the effects of functional group polyvalency on inhibitor activity. Our data emphasize the importance of an in-depth understanding of the mechanism(s) underlying 'concentration dependence' in inhibitor systems involving polyfunctional agents.
Subject(s)
Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/biosynthesis , Polyphenols/pharmacology , Vitis/chemistry , Amyloid beta-Peptides/ultrastructure , Animals , Benzothiazoles , Circular Dichroism , Cross-Linking Reagents , Fluorescent Dyes , Mice , Models, Molecular , Molecular Weight , Neurofibrillary Tangles/pathology , Polyphenols/chemistry , Protein Conformation , Seeds/chemistry , Structure-Activity Relationship , ThiazolesABSTRACT
Using first-principles density functional calculations, magnetically induced currents are obtained for zigzag single-walled carbon nanotubes. Clear differences and trends in current flow are observed between the different nanotube families. In particular, for a magnetic field applied along the tube axis, the current response of the λ = 0 infinite nanotubes is paramagnetic, whereas for λ = 1 and 2 nanotubes, the response is diamagnetic. The results are used to predict and interpret the significant changes in NMR properties for small molecules encapsulated inside a tube.
ABSTRACT
NMR parameters of (73)Ge and (17)O in vitreous GeO(2) and quartz GeO(2), including the isotropic shifts, the quadrupole coupling constants C(Q), and the electric-field-gradient asymmetry parameters η, are determined through density functional calculations. Clear correlations are established between (73)Ge shifts and the mean of the four neighboring Ge-O-Ge bond angles, and between C(Q) and η parameters of (17)O and the local Ge-O-Ge angle. Available experimental data for C(Q) and the corresponding established correlation are used to extract the value of 135° for the average Ge-O-Ge angle in vitreous GeO(2). The features of the Ge-O-Ge bond angle distribution of vitreous GeO(2) derived in this work are consistent with those inferred from other experimental probes.
