A5027136319- Mitochondrial Function and Pathology
- Ion channel regulation and function
- Enzyme Structure and Function
- ATP Synthase and ATPases Research
- Metabolomics and Mass Spectrometry Studies
- Ion Transport and Channel Regulation
- Amino Acid Enzymes and Metabolism
- RNA and protein synthesis mechanisms
- Protein Structure and Dynamics
- Metabolism and Genetic Disorders
- Photosynthetic Processes and Mechanisms
- Bacterial Genetics and Biotechnology
- Mass Spectrometry Techniques and Applications
- Neuroscience and Neuropharmacology Research
- Pancreatic function and diabetes
- Erythrocyte Function and Pathophysiology
- Cardiac electrophysiology and arrhythmias
- Lipid Membrane Structure and Behavior
- Receptor Mechanisms and Signaling
- Photoreceptor and optogenetics research
- Glycosylation and Glycoproteins Research
- Genetics and Neurodevelopmental Disorders
- Diet, Metabolism, and Disease
- Molecular Sensors and Ion Detection
- Electrochemical Analysis and Applications
University of California, Los Angeles
2015-2024
Tata Institute of Fundamental Research
2013-2018
Institute for Stem Cell Biology and Regenerative Medicine
2014-2018
National Centre for Biological Sciences
2013-2018
UCLA Health
2010-2017
Ludwig-Maximilians-Universität München
2014
University of California, San Francisco
2012
Centre National de la Recherche Scientifique
2008
Laboratoire de Chimie Physique
2008
Czech Academy of Sciences, Institute of Physiology
2007-2008
Membrane transport proteins that transduce free energy stored in electrochemical ion gradients into a concentration gradient are major class of membrane proteins. We report the crystal structure at 3.5 angstroms Escherichia coli lactose permease, an intensively studied member facilitator superfamily transporters. The molecule is composed N- and C-terminal domains, each with six transmembrane helices, symmetrically positioned within permease. A large internal hydrophilic cavity open to...
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 member solute symporters (SSS), Vibrio parahaemolyticus sodium/galactose symporter (vSGLT). The ∼3.0 angstrom contains 14 transmembrane (TM) helices an inward-facing conformation with core inverted repeats 5 TM (TM2 TM6 and TM7 TM11). Galactose is bound center core, occluded from outside solutions by hydrophobic residues....
The voltage-dependent anion channel (VDAC) constitutes the major pathway for entry and exit of metabolites across outer membrane mitochondria can serve as a scaffold molecules that modulate organelle. We report crystal structure beta-barrel eukaryotic protein, murine VDAC1 (mVDAC1) at 2.3 A resolution, revealing high-resolution image its architecture formed by 19 beta-strands. Unlike recent NMR human VDAC1, position voltage-sensing N-terminal segment is clearly resolved. alpha-helix oriented...
In recent years, there has been a vast increase in structural and functional understanding of VDAC1, but VDAC2 -3 have understudied despite having many unique phenotypes. One reason for the paucity biochemical characterization isoforms stems from inability obtaining purified, protein. Here we demonstrate expression, isolation, basic zebrafish (zfVDAC2). Further, resolved structure zfVDAC2 at 2.8 Å resolution, revealing crystallographic dimer. The dimer orientation was confirmed solution by...
The Na+/Ca2+ exchanger is a plasma membrane protein that regulates intracellular Ca2+ levels in cardiac myocytes. Transport activity governed by Ca2+, and the primary sensor (CBD1) located large cytoplasmic loop connecting two transmembrane helices. binding of to CBD1 sensory domain results conformational changes stimulate extrude Ca2+. Here, we present crystal structure at 2.5A resolution, which reveals novel site consisting four ions arranged tight planar cluster. This intricate...
The Na(+)-Ca(2+) exchanger plays a central role in cardiac contractility by maintaining Ca(2+) homeostasis. Two Ca(2+)-binding domains, CBD1 and CBD2, located large intracellular loop, regulate activity of the exchanger. binding to these regulatory domains activates transport across plasma membrane. Previously, we solved structure CBD1, revealing four ions arranged tight planar cluster. Here, present structures CBD2 Ca(2+)-bound (1.7-A resolution) -free (1.4-A conformations. Like has...
Orai1 and stromal interaction molecule (STIM)1 are critical components of Ca(2+) release-activated (CRAC) channels. is a pore subunit CRAC channels, STIM1 acts as an endoplasmic reticulum (ER) sensor that detects store depletion. Upon depletion after T-cell receptor stimulation, translocates coclusters with at sites close apposition the plasma membrane (PM) ER membrane. However, molecular these ER-PM junctions remain poorly understood. Using affinity protein purification, we uncovered...
Integral membrane proteins remain a challenge to proteomics because they contain domains with physicochemical properties poorly suited today's bottom-up protocols. These transmembrane regions may potentially post-translational modifications of functional significance, and thus development protocols for improved coverage in these is important. One way achieve this goal by using top-down mass spectrometry whereby the intact protein subjected dissociation. Here we describe high resolution...
Lactose permease of Escherichia coli (LacY) with a single-Cys residue in place A122 (helix IV) transports galactopyranosides and is specifically inactivated by methanethiosulfonyl-galactopyranosides (MTS-gal), which behave as unique suicide substrates. In order to study the mechanism inactivation more precisely, we solved structure single-Cys122 LacY complex covalently bound MTS-gal. This exhibits an inward-facing conformation similar that observed previously slight narrowing cytoplasmic...
Many pathogenic bacteria utilise sialic acids as an energy source or use them external coating to evade immune detection. As such, that colonise sialylated environments deploy specific transporters mediate import of scavenged acids. Here, we report a substrate-bound 1.95 Å resolution structure and subsequent characterisation SiaT, acid transporter from Proteus mirabilis. SiaT is secondary active the sodium solute symporter (SSS) family, which Na
Voltage-dependent anion channel-1 (VDAC1) is a highly regulated β-barrel membrane protein that mediates transport of ions and metabolites between the mitochondria cytosol cell. VDAC1 co-purifies with cholesterol functionally by cholesterol, among other endogenous lipids. Molecular modeling studies based on NMR observations have suggested five cholesterol-binding sites in VDAC1, but direct experimental evidence for these lacking. Here, to determine binding, we photolabeled purified mouse...
The voltage-dependent anion channel (VDAC) governs the free exchange of ions and metabolites between mitochondria rest cell. three-dimensional structure VDAC1 reveals a formed by 19 β-strands an N-terminal α-helix located near midpoint pore. position this causes narrowing cavity, but ample space for metabolite passage remains. participation N-terminus in voltage-gating process has been well established, molecular mechanism continues to be debated; however, majority models entail large...
Voltage-dependent anion channel (VDAC) is the major pathway for transport of ions and metabolites across mitochondrial outer membrane. Among three known mammalian VDAC isoforms, VDAC3 least characterized, but unique functional roles have been proposed in cellular animal models. Yet, a high-sequence similarity between VDAC1 indicative similar pore-forming structure. Here, we conclusively show that forms stable, highly conductive voltage-gated channels that, much like VDAC1, are weakly...
Significance Microcrystal electron diffraction (MicroED) is an cryo-microscopy (cryoEM) method for determining structures using submicron crystals. Until now, of membrane proteins by MicroED required that the protein crystals be in a solution amenable to standard cryoEM blotting and vitrification protocols. Here, we show microcrystals grown viscous bicelle mixture can become analyses modified procedures combined with focused ion-beam milling. Our findings provide basis solving embedded media MicroED.
Although the role of hydrophilic antioxidants in development hepatic insulin resistance and nonalcoholic fatty liver disease has been well studied, lipophilic remains poorly characterized. A known hydrogen peroxide scavenger is bilirubin, which can be oxidized to biliverdin then reduced back bilirubin by cytosolic reductase. Oxidation inside mitochondria must followed export cytosol, where bilirubin. Thus, putative mitochondrial exporter expected a major determinant regeneration...