A5067634666- Mitochondrial Function and Pathology
- Metabolism and Genetic Disorders
- ATP Synthase and ATPases Research
- RNA and protein synthesis mechanisms
- Probiotics and Fermented Foods
- Amino Acid Enzymes and Metabolism
- Parasitic Infections and Diagnostics
- Bacterial Genetics and Biotechnology
- Adipose Tissue and Metabolism
- Neuroscience and Neuropharmacology Research
- Protein Hydrolysis and Bioactive Peptides
- Muscle metabolism and nutrition
- Drug Transport and Resistance Mechanisms
- Photosynthetic Processes and Mechanisms
- Protein Structure and Dynamics
- Lipid Membrane Structure and Behavior
- Metabolomics and Mass Spectrometry Studies
- Parasitic infections in humans and animals
- Protist diversity and phylogeny
- Viral Infectious Diseases and Gene Expression in Insects
- Amoebic Infections and Treatments
- Advanced NMR Techniques and Applications
- Enzyme Structure and Function
- Diet and metabolism studies
- Photoreceptor and optogenetics research
MRC Mitochondrial Biology Unit
2016-2025
University of Cambridge
2015-2025
Medical Research Council
2016-2025
University of Stavanger
2024
Wellcome Trust
2005-2018
Wellcome Centre for Mitochondrial Research
2018
Newcastle University
2018
Children's Hospital of Philadelphia
2018
University of Pennsylvania
2018
Jean Mayer Human Nutrition Research Center on Aging
2018
The transport of pyruvate, the end product glycolysis, into mitochondria is an essential process that provides organelle with a major oxidative fuel. Although existence specific mitochondrial pyruvate carrier (MPC) has been anticipated, its molecular identity remained unknown. We report MPC heterocomplex formed by two members family previously uncharacterized membrane proteins are conserved from yeast to mammals. Members were found in inner membrane, and mutants lacking showed severe defects...
Mitochondrial ADP/ATP carriers transport ADP into the mitochondrial matrix for ATP synthesis, and out to fuel cell, by cycling between cytoplasmic-open matrix-open states. The structure of state is known, but it has proved difficult understand mechanism in absence a state. Here, we describe locked bongkrekic acid bound ADP/ATP-binding site at bottom central cavity. cytoplasmic side carrier closed conserved hydrophobic residues, salt bridge network, braced tyrosines. Glycine small amino...
Significance ADP/ATP carriers are archetypal members of the mitochondrial carrier family transport proteins, which thought to operate by a common but unresolved mechanism. Members this play key roles in many aspects cell physiology and implicated several severe human diseases. Here, we present structures Aac2p Aac3p, from Saccharomyces cerevisiae , determined X-ray crystallography. Together with mutagenesis functional assays, support an alternating-access mechanism involving domain-based...
The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. provides concise overviews, mostly tabular format, key properties approximately 1800 drug targets, and over 6000 interactions with about 3900 ligands. There an emphasis on selective pharmacology (where available), plus links open access knowledgebase source targets their ligands ( https://www.guidetopharmacology.org/ ), which more detailed views target ligand properties. Although constitutes...
Mitochondrial carriers link biochemical pathways in the cytosol and mitochondrial matrix by transporting substrates across inner membrane. Substrate recognition is specific for each carrier, but sequence similarities suggest have similar structures mechanisms of substrate translocation. By considering conservation amino acids, distance chemical constraints, modeling family members on known structure ADP/ATP translocase, we identified a common binding site. It explains selectivity proton...
The nucleotide sequence of a chromosomal DNA fragment Lactococcus lactis subsp. SSL135, previously implicated in peptide utilization, has been determined. genes oppDFBCA, encoding the oligopeptide transport system (Opp), and that endopeptidase PepO were located on this 8.9-kb fragment. oppDFBCA pepO are probably organized an operon. Analysis deduced amino acid sequences indicated consists two ATP-binding proteins OppD OppF, integral membrane OppB OppC, substrate-binding protein OppA. On...
The structures of mitochondrial transporters and uncoupling proteins are 3-fold pseudosymmetrical, but their substrates coupling ions not. Thus, deviations from symmetry to be expected in the substrate ion-binding sites central aqueous cavity. By analyzing pseudosymmetrical repeats which sequences made, conserved asymmetric residues were found cluster a region cavity identified previously as common substrate-binding site. Conserved symmetrical required for transport mechanism at...
The consumption of amino acids and peptides was monitored during growth in milk proteinase-positive (Prt+) -negative (Prt-) strains Lactococcus lactis. Prt- showed monophasic exponential growth, while the Prt+ grew two phases. first phases were same, no hydrolysis casein observed. Also, levels similar. At end this phase, not all free used, indicating that remaining unable to sustain growth. very low (about 5 mg/liter), suggesting these nitrogen sources play only a minor role Oligopeptide...
The transport activity of human mitochondrial aspartate/glutamate carriers is central to the malate-aspartate shuttle, urea cycle, gluconeogenesis and myelin synthesis. They have a unique three-domain structure, comprising calcium-regulated N-terminal domain with eight EF-hands, carrier domain, C-terminal domain. Here we present calcium-bound calcium-free structures N- domains, elucidating mechanism calcium regulation. Unexpectedly, EF-hands 4-8 are involved in dimerization form static unit,...
Abstract The acquisition of genes by horizontal transfer can impart entirely new biological functions and provide an important route to major evolutionary innovation. Here we have used ancient gene reconstruction functional assays investigate the impact a single horizontally transferred nucleotide transporter into common ancestor Microsporidia, radiation intracellular parasites animals humans. We show that this provided early microsporidians with ability steal host ATP become energy...
Mitochondrial uncoupling protein 1 (UCP1) gives brown adipose tissue of mammals its specialized ability to burn calories as heat for thermoregulation. When activated by fatty acids, UCP1 catalyzes the leak protons across mitochondrial inner membrane, short-circuiting mitochondrion generate heat, bypassing ATP synthesis. In contrast, purine nucleotides bind and inhibit UCP1, regulating proton a molecular mechanism that is unclear. We present cryo-electron microscopy structure GTP-inhibited...