The voltage-dependent anion channel (VDAC) constitutes the major pathway for the entry and exit of metabolites across the outer membrane of the mitochondria and can serve as a scaffold for molecules that modulate the organelle. We report the crystal structure of a -barrel eukaryotic membrane protein, the murine VDAC1 (mVDAC1) at 2.3 Å resolution, revealing a high-resolution image of its architecture formed by 19 -strands. Unlike the recent NMR structure of human VDAC1, the position of the voltagesensing N-terminal segment is clearly resolved. The ␣-helix of the N-terminal segment is oriented against the interior wall, causing a partial narrowing at the center of the pore. This segment is ideally positioned to regulate the conductance of ions and metabolites passing through the VDAC pore.-barrel ͉ mitochondria ͉ outer membrane protein ͉ ATP flux A ll eukaryotic cells require efficient exchange of metabolites between the cytoplasm and the mitochondria. This exchange is mediated by the most abundant protein in the outer mitochondrial membrane, the voltage-dependent anion channel (VDAC), which facilitates movement of ions and metabolites between the cytoplasm and the intermembrane space of the mitochondria. VDAC was first discovered in 1976 (1) and has since been extensively studied by a number of biochemical and biophysical techniques demonstrating its conserved properties of voltage gating and ion selectivity and its ability to act as a scaffold for modulator proteins from both sides of the outer membrane (2, 3).Single-channel conductance experiments on VDAC1 at low membrane potential (10 mV) show a high conductance indicative of a large pore, often referred to as the open state of the channel (2). As voltage is increased (Ͼ30 mV) in either a positive or negative direction, a lower conductance, ostensibly the closed state, is obtained. Endogenous potentials caused by chemical gradients across the outer membrane [Donnan potentials (4)] may thus be sufficient to regulate this channel. Although the nature of either of these states is unknown in the absence of structural data, transition between them presumably involves conformational changes constituting a gating action that hinders the passage of metabolites such as adenine nucleotides. Furthermore, this transition is associated with altered ion selectivity because the channel shifts from weakly anion selective to weakly cation selective as it moves from open to closed. This complex gating behavior has driven numerous investigations that have provided sometimes contradictory findings; however, the role of VDAC to regulate metabolite traffic across the outer membrane is firmly established.As the major pathway into and out of mitochondria, VDAC mediates an intimate dichotomy between metabolism and death in all cells (5). Mitochondrial-dependent cell death involves numerous proteins [including hexokinase (6) and the Bcl-2 family of proteins (7), in particular] that alternatively promote or prevent mitochondrial dysfunction through interaction with, and potentially m...
Membrane transporters that use energy stored in sodium gradients to drive nutrients into cells constitute a major class of proteins. We report the crystal structure of a member of the solute sodium symporters (SSS), the Vibrio parahaemolyticus sodium/galactose symporter (vSGLT). The ~3.0Å structure contains 14 transmembrane helices in an inward facing conformation with a core structure of inverted repeats of 5 TM helices (TM2-TM6 and TM7-TM11). Galactose is bound in the center of the core, occluded from the outside solutions by hydrophobic residues. Surprisingly, the architecture of the core is similar to the leucine transporter (LeuT) from a different gene family. Modeling the outward-facing conformation based on the LeuT structure, in conjunction with biophysical data, provides insight into structural rearrangements for active transport.
Crystal structures of heparin-derived tetra- and hexasaccharides complexed with basic fibroblast growth factor (bFGF) were determined at resolutions of 1.9 and 2.2 angstroms, respectively. The heparin structure may be approximated as a helical polymer with a disaccharide rotation of 174 degrees and a translation of 8.6 angstroms along the helix axis. Both molecules bound similarly to a region of the bFGF surface containing residues asparagine-28, arginine-121, lysine-126, and glutamine-135, the hexasaccharide also interacted with an additional binding site formed by lysine-27, asparagine-102, and lysine-136. No significant conformational change in bFGF occurred upon heparin oligosaccharide binding, which suggests that heparin primarily serves to juxtapose components of the FGF signal transduction pathway.
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