Nanoscale architecture of a VAP-A–OSBP tethering complex at membrane contact sites. In situ architecture of the lipid transport protein VPS13C at ER–lysosome membrane contacts. A phosphatidylinositol-4-phosphate powered exchange mechanism to create a lipid gradient between membranes. Moser von Filseck, J., Vanni, S., Mesmin, B., Antonny, B. Membrane hydrophobicity determines the activation free energy of passive lipid transport. Cryo-EM reconstruction of a VPS13 fragment reveals a long groove to channel lipids between membranes. Emr1 regulates the number of foci of the endoplasmic reticulum–mitochondria encounter structure complex. The conserved GTPase Gem1 regulates endoplasmic reticulum–mitochondria connections. Highly accurate protein structure prediction with AlphaFold. Improved prediction of protein-protein interactions using AlphaFold2. Genome-wide localization study of yeast Pex11 identifies peroxisome-mitochondria interactions through the ERMES complex. Peroxisomes are juxtaposed to strategic sites on mitochondria. Preparing samples from whole cells using focused-ion-beam milling for cryo-electron tomography. Composition and topology of the endoplasmic reticulum-mitochondria encounter structure. Separating mitochondrial protein assembly and endoplasmic reticulum tethering by selective coupling of Mdm10. Precise tracking of the dynamics of multiple proteins in endocytic events. Visualizing the functional architecture of the endocytic machinery. Picco, A., Mund, M., Ries, J., Nedelec, F. Crystal structure of Mdm12 reveals the architecture and dynamic organization of the ERMES complex. Tricalbins contribute to cellular lipid flux and form curved ER–PM contacts that are bridged by rod-shaped structures. Crystal structures of Mmm1 and Mdm12–Mmm1 reveal mechanistic insight into phospholipid trafficking at ER–mitochondria contact sites. Lipid transport by TMEM24 at ER–plasma membrane contacts regulates pulsatile insulin secretion. Conserved SMP domains of the ERMES complex bind phospholipids and mediate tether assembly. Structure of a lipid-bound extended synaptotagmin indicates a role in lipid transfer. Tubular lipid binding proteins (TULIPs) growing everywhere. A conserved membrane-binding domain targets proteins to organelle contact sites. Homology of SMP domains to the TULIP superfamily of lipid-binding proteins provides a structural basis for lipid exchange between ER and mitochondria. ER-associated mitochondrial division links the distribution of mitochondria and mitochondrial DNA in yeast. Coming together to define membrane contact sites. Mechanisms of nonvesicular lipid transport. METALIC reveals interorganelle lipid flux in live cells by enzymatic mass tagging. Structure-function insights into direct lipid transfer between membranes by Mmm1-Mdm12 of ERMES. An ER-mitochondria tethering complex revealed by a synthetic biology screen. Association between the endoplasmic reticulum and mitochondria of yeast facilitates interorganelle transport of phospholipids through membrane contact. Newly made phosphatidylserine and phosphatidylethanolamine are preferentially translocated between rat liver mitochondria and endoplasmic reticulum. Phospholipid synthesis in a membrane fraction associated with mitochondria. These findings resolve the in situ supramolecular architecture of a major inter-organelle lipid transfer machinery and provide a basis for the mechanistic understanding of lipid fluxes in eukaryotic cells. Our molecular model of ERMES reveals a pathway for lipids. Each bridge consists of three synaptotagmin-like mitochondrial lipid binding protein domains oriented in a zig-zag arrangement. We found that ERMES assembles into approximately 25 discrete bridge-like complexes distributed irregularly across a contact site. Here we determined the molecular organization of ERMES within Saccharomyces cerevisiae cells using integrative structural biology by combining quantitative live imaging, cryo-correlative microscopy, subtomogram averaging and molecular modelling. In yeast, tethering and lipid transfer between the two organelles is mediated by the endoplasmic reticulum–mitochondria encounter structure (ERMES), a four-subunit complex of unresolved stoichiometry and architecture 4, 5, 6. The endoplasmic reticulum and mitochondria are main hubs of eukaryotic membrane biogenesis that rely on lipid exchange via membrane contact sites 1, 2, 3, but the underpinning mechanisms remain poorly understood.
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