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https://www.readbyqxmd.com/read/29229838/architecture-of-the-human-pi4kiii%C3%AE-lipid-kinase-complex
#1
Joshua A Lees, Yixiao Zhang, Michael S Oh, Curtis M Schauder, Xiaoling Yu, Jeremy M Baskin, Kerry Dobbs, Luigi D Notarangelo, Pietro De Camilli, Thomas Walz, Karin M Reinisch
Plasma membrane (PM) phosphoinositides play essential roles in cell physiology, serving as both markers of membrane identity and signaling molecules central to the cell's interaction with its environment. The first step in PM phosphoinositide synthesis is the conversion of phosphatidylinositol (PI) to PI4P, the precursor of PI(4,5)P2 and PI(3,4,5)P3 This conversion is catalyzed by the PI4KIIIα complex, comprising a lipid kinase, PI4KIIIα, and two regulatory subunits, TTC7 and FAM126. We here report the structure of this complex at 3...
December 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/29222176/ca2-releases-e-syt1-autoinhibition-to-couple-er-plasma-membrane-tethering-with-lipid-transport
#2
Xin Bian, Yasunori Saheki, Pietro De Camilli
The extended synaptotagmins (E-Syts) are endoplasmic reticulum (ER) proteins that bind the plasma membrane (PM) via C2 domains and transport lipids between them via SMP domains. E-Syt1 tethers and transports lipids in a Ca2+-dependent manner, but the role of Ca2+ in this regulation is unclear. Of the five C2 domains of E-Syt1, only C2A and C2C contain Ca2+-binding sites. Using liposome-based assays, we show that Ca2+ binding to C2C promotes E-Syt1-mediated membrane tethering by releasing an inhibition that prevents C2E from interacting with PI(4,5)P2-rich membranes, as previously suggested by studies in semi-permeabilized cells...
December 8, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29089042/membrane-dynamics-and-organelle-biogenesis-lipid-pipelines-and-vesicular-carriers
#3
EDITORIAL
Christopher J Stefan, William S Trimble, Sergio Grinstein, Guillaume Drin, Karin Reinisch, Pietro De Camilli, Sarah Cohen, Alex M Valm, Jennifer Lippincott-Schwartz, Tim P Levine, David B Iaea, Frederick R Maxfield, Clare E Futter, Emily R Eden, Delphine Judith, Alexander R van Vliet, Patrizia Agostinis, Sharon A Tooze, Ayumu Sugiura, Heidi M McBride
Discoveries spanning several decades have pointed to vital membrane lipid trafficking pathways involving both vesicular and non-vesicular carriers. But the relative contributions for distinct membrane delivery pathways in cell growth and organelle biogenesis continue to be a puzzle. This is because lipids flow from many sources and across many paths via transport vesicles, non-vesicular transfer proteins, and dynamic interactions between organelles at membrane contact sites. This forum presents our latest understanding, appreciation, and queries regarding the lipid transport mechanisms necessary to drive membrane expansion during organelle biogenesis and cell growth...
October 31, 2017: BMC Biology
https://www.readbyqxmd.com/read/29083305/single-molecule-force-spectroscopy-of-protein-membrane-interactions
#4
Lu Ma, Yiying Cai, Yanghui Li, Junyi Jiao, Zhenyong Wu, Ben O'Shaughnessy, Pietro De Camilli, Erdem Karatekin, Yongli Zhang
Many biological processes rely on protein-membrane interactions in the presence of mechanical forces, yet high resolution methods to quantify such interactions are lacking. Here, we describe a single-molecule force spectroscopy approach to quantify membrane binding of C2 domains in Synaptotagmin-1 (Syt1) and Extended Synaptotagmin-2 (E-Syt2). Syts and E-Syts bind the plasma membrane via multiple C2 domains, bridging the plasma membrane with synaptic vesicles or endoplasmic reticulum to regulate membrane fusion or lipid exchange, respectively...
October 30, 2017: ELife
https://www.readbyqxmd.com/read/28933693/structural-inhibition-of-dynamin-mediated-membrane-fission-by-endophilin
#5
Annika Hohendahl, Nathaniel Talledge, Valentina Galli, Peter S Shen, Frédéric Humbert, Pietro De Camilli, Adam Frost, Aurélien Roux
Dynamin, which mediates membrane fission during endocytosis, binds endophilin and other members of the Bin-Amphiphysin-Rvs (BAR) protein family. How endophilin influences endocytic membrane fission is still unclear. Here, we show that dynamin-mediated membrane fission is potently inhibited in vitro when an excess of endophilin co-assembles with dynamin around membrane tubules. We further show by electron microscopy that endophilin intercalates between turns of the dynamin helix and impairs fission by preventing trans interactions between dynamin rungs that are thought to play critical roles in membrane constriction...
September 21, 2017: ELife
https://www.readbyqxmd.com/read/28559323/contacts-between-the-endoplasmic-reticulum-and-other-membranes-in-neurons
#6
Yumei Wu, Christina Whiteus, C Shan Xu, Kenneth J Hayworth, Richard J Weinberg, Harald F Hess, Pietro De Camilli
Close appositions between the membrane of the endoplasmic reticulum (ER) and other intracellular membranes have important functions in cell physiology. These include lipid homeostasis, regulation of Ca(2+) dynamics, and control of organelle biogenesis and dynamics. Although these membrane contacts have previously been observed in neurons, their distribution and abundance have not been systematically analyzed. Here, we have used focused ion beam-scanning electron microscopy to generate 3D reconstructions of intracellular organelles and their membrane appositions involving the ER (distance ≤30 nm) in different neuronal compartments...
June 13, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28466468/loss-of-dynamin-2-gtpase-function-results-in-microcytic-anaemia
#7
Fiona C Brown, Michael Collett, Cedric S Tremblay, Gerhard Rank, Pietro De Camilli, Carmen J Booth, Marc Bitoun, Phillip J Robinson, Benjamin T Kile, Stephen M Jane, David J Curtis
In a dominant mouse ethylnitrosurea mutagenesis screen for genes regulating erythropoiesis, we identified a pedigree with a novel microcytic hypochromia caused by a V235G missense mutation in Dynamin 2 (Dnm2). Mutations in Dnm2, a GTPase, are highly disease-specific and have been implicated in four forms of human diseases: centronuclear myopathy, Charcot-Marie Tooth neuropathy and, more recently, T-cell leukaemia and Hereditary Spastic Paraplegia, but red cell abnormalities have not been reported to date. The V235G mutation lies within a crucial GTP nucleotide-binding pocket of Dnm2, and resulted in defective GTPase activity and incompatibility with life in the homozygous state...
August 2017: British Journal of Haematology
https://www.readbyqxmd.com/read/28363589/the-extended-synaptotagmins
#8
REVIEW
Yasunori Saheki, Pietro De Camilli
The extended-synaptotagmins (tricalbins in yeast) derive their name from their partial domain structure similarity to the synaptotagmins, which are characterized by an N-terminal membrane anchor and cytosolically exposed C2 domains. However, they differ from the synaptotagmins in localization and function. The synaptotagmins tether secretory vesicles, including synaptic vesicles, to the plasma membrane (PM) via their C2 domains and regulate their Ca(2+) triggered exocytosis. In contrast, the extended-synaptotagmins are resident proteins of the endoplasmic reticulum (ER), which tether this organelle to the plasma membrane via their C2 domains, but not as a premise to fusion of the two membranes...
September 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28301744/endoplasmic-reticulum-plasma-membrane-contact-sites
#9
REVIEW
Yasunori Saheki, Pietro De Camilli
The endoplasmic reticulum (ER) has a broad localization throughout the cell and forms direct physical contacts with all other classes of membranous organelles, including the plasma membrane (PM). A number of protein tethers that mediate these contacts have been identified, and study of these protein tethers has revealed a multiplicity of roles in cell physiology, including regulation of intracellular Ca(2+) dynamics and signaling as well as control of lipid traffic and homeostasis. In this review, we discuss the cross talk between the ER and the PM mediated by direct contacts...
June 20, 2017: Annual Review of Biochemistry
https://www.readbyqxmd.com/read/28279363/synaptic-vesicle-clusters-at-synapses-a-distinct-liquid-phase
#10
REVIEW
Dragomir Milovanovic, Pietro De Camilli
Phase separation in the cytoplasm is emerging as a major principle in intracellular organization. In this process, sets of macromolecules assemble themselves into liquid compartments that are distinct from the surrounding medium but are not delimited by membrane boundaries. Here, we discuss how phase separation, in which a component of one of the two phases is vesicles rather than macromolecules, could underlie the formation of synaptic vesicle (SV) clusters in proximity to presynaptic sites. The organization of SVs into a liquid phase could explain how SVs remain tightly clustered without being stably bound to a scaffold so that they can be efficiently recruited to release site by active zone components...
March 8, 2017: Neuron
https://www.readbyqxmd.com/read/28231468/parkinson-sac-domain-mutation-in-synaptojanin-1-impairs-clathrin-uncoating-at-synapses-and-triggers-dystrophic-changes-in-dopaminergic-axons
#11
Mian Cao, Yumei Wu, Ghazaleh Ashrafi, Amber J McCartney, Heather Wheeler, Eric A Bushong, Daniela Boassa, Mark H Ellisman, Timothy A Ryan, Pietro De Camilli
Synaptojanin 1 (SJ1) is a major presynaptic phosphatase that couples synaptic vesicle endocytosis to the dephosphorylation of PI(4,5)P2, a reaction needed for the shedding of endocytic factors from their membranes. While the role of SJ1's 5-phosphatase module in this process is well recognized, the contribution of its Sac phosphatase domain, whose preferred substrate is PI4P, remains unclear. Recently a homozygous mutation in its Sac domain was identified in early-onset parkinsonism patients. We show that mice carrying this mutation developed neurological manifestations similar to those of human patients...
February 22, 2017: Neuron
https://www.readbyqxmd.com/read/28209843/lipid-transport-by-tmem24-at-er-plasma-membrane-contacts-regulates-pulsatile-insulin-secretion
#12
Joshua A Lees, Mirko Messa, Elizabeth Wen Sun, Heather Wheeler, Federico Torta, Markus R Wenk, Pietro De Camilli, Karin M Reinisch
Insulin is released by β cells in pulses regulated by calcium and phosphoinositide signaling. Here, we describe how transmembrane protein 24 (TMEM24) helps coordinate these signaling events. We showed that TMEM24 is an endoplasmic reticulum (ER)-anchored membrane protein whose reversible localization to ER-plasma membrane (PM) contacts is governed by phosphorylation and dephosphorylation in response to oscillations in cytosolic calcium. A lipid-binding module in TMEM24 transports the phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] precursor phosphatidylinositol between bilayers, allowing replenishment of PI(4,5)P2 hydrolyzed during signaling...
February 17, 2017: Science
https://www.readbyqxmd.com/read/28035045/multiphasic-dynamics-of-phosphatidylinositol-4-phosphate-during-phagocytosis
#13
Roni Levin, Gerald R V Hammond, Tamas Balla, Pietro De Camilli, Gregory D Fairn, Sergio Grinstein
We analyzed the distribution, fate, and functional role of phosphatidylinositol 4-phosphate (PtdIns4P) during phagosome formation and maturation. To this end, we used genetically encoded probes consisting of the PtdIns4P-binding domain of the bacterial effector SidM. PtdIns4P was found to undergo complex, multiphasic changes during phagocytosis. The phosphoinositide, which is present in the plasmalemma before engagement of the target particle, is transiently enriched in the phagosomal cup. Soon after the phagosome seals, PtdIns4P levels drop precipitously due to the hydrolytic activity of Sac2 and phospholipase C, becoming undetectable for ∼10 min...
January 1, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/27895154/kidney-tubular-ablation-of-ocrl-inpp5b-phenocopies-lowe-syndrome-tubulopathy
#14
Kazunori Inoue, Daniel M Balkin, Lijuan Liu, Ramiro Nandez, Yumei Wu, Xuefei Tian, Tong Wang, Robert Nussbaum, Pietro De Camilli, Shuta Ishibe
Lowe syndrome and Dent disease are two conditions that result from mutations of the inositol 5-phosphatase oculocerebrorenal syndrome of Lowe (OCRL) and share the feature of impaired kidney proximal tubule function. Genetic ablation of Ocrl in mice failed to recapitulate the human phenotypes, possibly because of the redundant functions of OCRL and its paralog type 2 inositol polyphosphate-5-phosphatase (INPP5B). Germline knockout of both paralogs in mice results in early embryonic lethality. We report that kidney tubule-specific inactivation of Inpp5b on a global Ocrl-knockout mouse background resulted in low molecular weight proteinuria, phosphaturia, and acidemia...
May 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/27670760/membrane-fission-by-dynamin-what-we-know-and-what-we-need-to-know
#15
REVIEW
Bruno Antonny, Christopher Burd, Pietro De Camilli, Elizabeth Chen, Oliver Daumke, Katja Faelber, Marijn Ford, Vadim A Frolov, Adam Frost, Jenny E Hinshaw, Tom Kirchhausen, Michael M Kozlov, Martin Lenz, Harry H Low, Harvey McMahon, Christien Merrifield, Thomas D Pollard, Phillip J Robinson, Aurélien Roux, Sandra Schmid
The large GTPase dynamin is the first protein shown to catalyze membrane fission. Dynamin and its related proteins are essential to many cell functions, from endocytosis to organelle division and fusion, and it plays a critical role in many physiological functions such as synaptic transmission and muscle contraction. Research of the past three decades has focused on understanding how dynamin works. In this review, we present the basis for an emerging consensus on how dynamin functions. Three properties of dynamin are strongly supported by experimental data: first, dynamin oligomerizes into a helical polymer; second, dynamin oligomer constricts in the presence of GTP; and third, dynamin catalyzes membrane fission upon GTP hydrolysis...
November 2, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27435091/loss-of-synj1-dual-phosphatase-activity-leads-to-early-onset-refractory-seizures-and-progressive-neurological-decline
#16
Katia Hardies, Yiying Cai, Claude Jardel, Anna C Jansen, Mian Cao, Patrick May, Tania Djémié, Caroline Hachon Le Camus, Kathelijn Keymolen, Tine Deconinck, Vikas Bhambhani, Catherine Long, Samin A Sajan, Katherine L Helbig, Arvid Suls, Rudi Balling, Ingo Helbig, Peter De Jonghe, Christel Depienne, Pietro De Camilli, Sarah Weckhuysen
SYNJ1 encodes a polyphosphoinositide phosphatase, synaptojanin 1, which contains two consecutive phosphatase domains and plays a prominent role in synaptic vesicle dynamics. Autosomal recessive inherited variants in SYNJ1 have previously been associated with two different neurological diseases: a recurrent homozygous missense variant (p.Arg258Gln) that abolishes Sac1 phosphatase activity was identified in three independent families with early onset parkinsonism, whereas a homozygous nonsense variant (p.Arg136*) causing a severe decrease of mRNA transcript was found in a single patient with intractable epilepsy and tau pathology...
September 2016: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/27419871/endosome-er-contacts-control-actin-nucleation-and-retromer-function-through-vap-dependent-regulation-of-pi4p
#17
Rui Dong, Yasunori Saheki, Sharan Swarup, Louise Lucast, J Wade Harper, Pietro De Camilli
VAP (VAPA and VAPB) is an evolutionarily conserved endoplasmic reticulum (ER)-anchored protein that helps generate tethers between the ER and other membranes through which lipids are exchanged across adjacent bilayers. Here, we report that by regulating PI4P levels on endosomes, VAP affects WASH-dependent actin nucleation on these organelles and the function of the retromer, a protein coat responsible for endosome-to-Golgi traffic. VAP is recruited to retromer budding sites on endosomes via an interaction with the retromer SNX2 subunit...
July 14, 2016: Cell
https://www.readbyqxmd.com/read/27252358/the-endocytic-activity-of-the-flagellar-pocket-in-trypanosoma-brucei-is-regulated-by-an-adjacent-phosphatidylinositol-phosphate-kinase
#18
Lars Demmel, Katy Schmidt, Louise Lucast, Katharina Havlicek, Armin Zankel, Tina Koestler, Viktoria Reithofer, Pietro de Camilli, Graham Warren
No abstract text is available yet for this article.
June 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27065097/control-of-plasma-membrane-lipid-homeostasis-by-the-extended-synaptotagmins
#19
Yasunori Saheki, Xin Bian, Curtis M Schauder, Yujin Sawaki, Michal A Surma, Christian Klose, Frederic Pincet, Karin M Reinisch, Pietro De Camilli
Acute metabolic changes in plasma membrane (PM) lipids, such as those mediating signalling reactions, are rapidly compensated by homeostatic responses whose molecular basis is poorly understood. Here we show that the extended synaptotagmins (E-Syts), endoplasmic reticulum (ER) proteins that function as PtdIns(4,5)P2- and Ca(2+)-regulated tethers to the PM, participate in these responses. E-Syts transfer glycerolipids between bilayers in vitro, and this transfer requires Ca(2+) and their lipid-harbouring SMP domain...
May 2016: Nature Cell Biology
https://www.readbyqxmd.com/read/26686281/smp-domain-proteins-at-membrane-contact-sites-structure-and-function
#20
REVIEW
Karin M Reinisch, Pietro De Camilli
SMP-domains are found in proteins that localize to membrane contact sites. Elucidation of the properties of these proteins gives clues as to the molecular bases underlying processes that occur at such sites. Described here are recent discoveries concerning the structure, function, and regulation of the Extended-Synaptotagmin proteins and ERMES complex subunits, SMP-domain proteins at endoplasmic reticulum (ER)-plasma membrane and ER-mitochondrial contacts, respectively. They act as tethers contributing to the architecture of these sites and as lipid transporters that convey glycerolipids between apposed membranes...
August 2016: Biochimica et Biophysica Acta
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