A5004434143- Lipid Membrane Structure and Behavior
- Sphingolipid Metabolism and Signaling
- Cellular transport and secretion
- Erythrocyte Function and Pathophysiology
- ATP Synthase and ATPases Research
- Lysosomal Storage Disorders Research
- Endoplasmic Reticulum Stress and Disease
- Photosynthetic Processes and Mechanisms
- Lipid metabolism and biosynthesis
- Metabolism and Genetic Disorders
- Mitochondrial Function and Pathology
- Drug Transport and Resistance Mechanisms
- Autophagy in Disease and Therapy
- Caveolin-1 and cellular processes
- Plant Reproductive Biology
- RNA and protein synthesis mechanisms
- Carbohydrate Chemistry and Synthesis
- Biotin and Related Studies
- Ion Transport and Channel Regulation
- Click Chemistry and Applications
- Toxoplasma gondii Research Studies
- Protein Structure and Dynamics
- Ubiquitin and proteasome pathways
- Phagocytosis and Immune Regulation
- Porphyrin and Phthalocyanine Chemistry
Osnabrück University
2016-2025
Utrecht University
2009-2019
Amherst College
2009
Institute of Molecular Life Sciences
2003-2007
Amsterdam UMC Location University of Amsterdam
2000-2003
University of Amsterdam
2000-2001
Radboud University Nijmegen
1994-1999
MRC Laboratory of Molecular Biology
1998
Medical Research Council
1998
Dutch Blood Transfusion Society
1994
Ceramides draw wide attention as tumor suppressor lipids that act directly on mitochondria to trigger apoptotic cell death. However, molecular details of the underlying mechanism are largely unknown. Using a photoactivatable ceramide probe, we here identify voltage-dependent anion channels VDAC1 and VDAC2 mitochondrial binding proteins. Coarse-grain dynamics simulations reveal both harbor site one side barrel wall. This includes membrane-buried glutamate mediates direct contact with head...
Lysosomes are vital organelles vulnerable to injuries from diverse materials. Failure repair or sequester damaged lysosomes poses a threat cell viability. Here we report that cells exploit sphingomyelin-based lysosomal pathway operates independently of ESCRT reverse potentially lethal membrane damage. Various conditions perturbing organelle integrity trigger rapid calcium-activated scrambling and cytosolic exposure sphingomyelin. Subsequent metabolic conversion sphingomyelin by neutral...
Plasma membranes in eukaryotic cells display asymmetric lipid distributions with aminophospholipids concentrated the inner and sphingolipids outer leaflet. This asymmetry is maintained by ATP-driven transporters whose identities are unknown. The yeast plasma membrane contains two P-type ATPases, Dnf1p Dnf2p, structural similarity to ATPase II, a candidate aminophospholipid translocase from bovine chromaffin granules. Loss of Dnf2p virtually abolished ATP-dependent transport NBD-labeled...
Sphingomyelin (SM) is a vital component of cellular membranes in organisms ranging from mammals to protozoa. Its production involves the transfer phosphocholine phosphatidylcholine ceramide, yielding diacylglycerol process. The mammalian genome encodes two known SM synthase (SMS) isoforms, SMS1 and SMS2. However, relative contributions these enzymes cells remained be established. Here we show that SMS2 are co-expressed variety cell types function as key Golgi- plasma membrane-associated...
Ceramides are central intermediates of sphingolipid metabolism with critical functions in cell organization and survival. They synthesized on the cytosolic surface endoplasmic reticulum (ER) transported by ceramide transfer protein to Golgi for conversion sphingomyelin (SM) SM synthase SMS1. In this study, we report identification an SMS1-related (SMSr) enzyme, which catalyses synthesis analogue phosphoethanolamine (CPE) ER lumen. Strikingly, SMSr produces only trace amounts CPE, i.e.,...
Members of the P(4) subfamily P-type ATPases catalyze phospholipid transport and create membrane lipid asymmetry in late secretory endocytic compartments. usually pump small cations mechanism involved appears conserved throughout family. How this is adapted to flip phospholipids remains be established. P(4)-ATPases form heteromeric complexes with CDC50 proteins. Dissociation yeast P(4)-ATPase Drs2p from its binding partner Cdc50p disrupts catalytic activity (Lenoir, G., Williamson, P., Puts,...
Members of the P(4) subfamily P-type ATPases are believed to catalyze transport phospholipids across cellular bilayers. However, most pump small cations or metal ions, and atomic structures revealed a mechanism that is conserved throughout family. Hence, challenging problem understand how this adapted in P(4)-ATPases flip phospholipids. form heteromeric complexes with Cdc50 proteins. The primary role these additional polypeptides unknown. Here, we show affinity yeast P(4)-ATPase Drs2p for...
Bifunctional lipid technology: Cells convert externally added photoactivatable and "clickable" fatty acids into a variety of bifunctional phospholipids that can be covalently linked to their protein-binding partners by irradiation with UV light. Derivatization the clickable group reporter molecule makes it possible identify image lipid-bound proteins in situ (see scheme). As service our authors readers, this journal provides supporting information supplied authors. Such materials are peer...
Mitochondria are double-membrane-bounded organelles that depend critically on phospholipids supplied by the endoplasmic reticulum. These lipids must cross outer membrane to support mitochondrial function, but how they do this is unclear. We identify Voltage Dependent Anion Channel (VDAC), an abundant protein, as a scramblase-type lipid transporter catalyzes entry. On reconstitution into vesicles, dimers of human VDAC1 and VDAC2 catalyze rapid transbilayer translocation mechanism unrelated...
Eukaryotic plasma membranes generally display asymmetric lipid distributions with the aminophospholipids concentrated in cytosolic leaflet. This arrangement is maintained by aminophospholipid translocases (APLTs) that use ATP hydrolysis to flip phosphatidylserine (PS) and phosphatidylethanolamine (PE) from external The identity of APLTs has not been established, but prime candidates are members P4 subfamily P-type ATPases. Removal ATPases Dnf1p Dnf2p budding yeast abolishes inward...
High levels of the neuron-specific protein kinase C substrate, B-50 (= GAP43), are present in neurites and growth cones during neuronal development regeneration. This suggests a hitherto nonelucidated role this neurite outgrowth. Comparable high arise pheochromocytoma PC12 cell line formation. To get insight putative growth-associated function B-50, we compared its ultrastructural localization naive cells with distribution nerve factor (NGF)- or dibutyryl cyclic AMP (dbcAMP)-treated cells....
Sphingomyelin (SM) is a vital component of mammalian membranes, providing mechanical stability and structural framework for plasma membrane organization. Its production involves the transfer phosphocholine from phosphatidylcholine onto ceramide, reaction catalyzed by SM synthase in Golgi lumen. Drosophila lacks instead synthesizes analogue ceramide phosphoethanolamine (CPE) as principal sphingolipid. The corresponding CPE shares mechanistic features with enzymes mediating phospholipid...
A deregulation of ceramide biosynthesis in the endoplasmic reticulum (ER) is frequently linked to induction mitochondrial apoptosis. Although vitro studies suggest that ceramides might initiate cell death by acting directly on mitochondria, their actual contribution apoptotic response living cells unclear. Here, we have analyzed consequences targeting biosynthetic flow mitochondria using a transfer protein (encoded COL4A3BP) equipped with an OMM anchor, mitoCERT. Cells expressing mitoCERT...
Mechanisms leading to osteoporosis are incompletely understood. Genetic disorders with skeletal fragility provide insight into metabolic pathways contributing bone strength. We evaluated 6 families rare phenotypes and by next-generation sequencing. In all the families, we identified a heterozygous variant in SGMS2, gene prominently expressed cortical encoding plasma membrane-resident sphingomyelin synthase SMS2. Four unrelated shared same nonsense variant, c.148C>T (p.Arg50*), whereas other...