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Molecular Biology of the Cell

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https://www.readbyqxmd.com/read/28814508/dynamic-functional-assembly-of-the-torsin-aaa-atpase-and-its-modulation-by-lap1
#1
Anna R Chase, Ethan Laudermilch, Jimin Wang, Hideki Shigematsu, Takeshi Yokoyama, Christian Schlieker
TorsinA is an essential AAA+ ATPase requiring LAP1 or LULL1 as cofactors. The dynamics of the Torsin/cofactor system remain poorly understood, with previous models invoking Torsin/cofactor assemblies with fixed stoichiometries. Here, we demonstrate that TorsinA assembles into homotypic oligomers in the presence of ATP. Torsin variants mutated at the 'back' interface disrupt homo-oligomerization but still show robust ATPase activity in the presence of its cofactors. These Torsin mutants are severely compromised in their ability to rescue nuclear envelope defects in Torsin-deficient cells, suggesting that TorsinA homo-oligomers play a key role in vivo Engagement of the oligomer by LAP1 triggers ATP hydrolysis and rapid complex disassembly...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814507/systematic-gene-tagging-using-crispr-cas9-in-human-stem-cells-to-illuminate-cell-organization
#2
Brock Roberts, Amanda Haupt, Andrew Tucker, Tanya Grancharova, Joy Arakaki, Margaret A Fuqua, Angelique Nelson, Caroline Hookway, Susan A Ludmann, Irina A Mueller, Ruian Yang, Alan R Horwitz, Susanne M Rafelski, Ruwanthi N Gunawardane
We present a CRISPR/Cas9 genome editing strategy to systematically tag endogenous proteins with fluorescent tags in human induced pluripotent stem cells. To date we have generated multiple human iPSC lines with monoallelic GFP tags labeling 10 proteins representing major cellular structures. The tagged proteins include alpha tubulin, beta actin, desmoplakin, fibrillarin, nuclear lamin B1, non-muscle myosin heavy chain IIB, paxillin, Sec61 beta, tight junction protein ZO1, and Tom20. Our genome editing methodology using Cas9/crRNA ribonuclear protein and donor plasmid co-electroporation, followed by fluorescence-based enrichment of edited cells, typically resulted in <0...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814506/role-of-clathrin-in-dense-core-vesicle-biogenesis
#3
Bhavani S Sahu, Paul T Manna, James R Edgar, Robin Antrobus, Sushil K Mahata, Alessandro Bartolomucci, Georg H H Borner, Margaret S Robinson
The dense-core vesicles (DCVs) of neuroendocrine cells are a rich source of bioactive molecules such as peptides, hormones, and neurotransmitters, but relatively little is known about how they are formed. Using fractionation profiling, a method that combines subcellular fractionation with mass spectrometry, we identified ∼1200 proteins in PC12 cell vesicle-enriched fractions, with DCV-associated proteins showing distinct profiles from proteins associated with other types of vesicles. To investigate the role of clathrin in DCV biogenesis, we stably transduced PC12 cells with an inducible shRNA targeting clathrin heavy chain, resulting in ∼85% protein loss...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814505/the-molecular-architecture-of-the-yeast-spindle-pole-body-core-determined-by-bayesian-integrative-modeling
#4
Shruthi Viswanath, Massimiliano Bonomi, Seung Joong Kim, Vadim A Klenchin, Keenan C Taylor, King C Yabut, Neil T Umbreit, Heather A Van Epps, Janet Meehl, Michele H Jones, Daniel Russel, Javier A Velazquez-Muriel, Mark Winey, Ivan Rayment, Trisha N Davis, Andrej Sali, Eric G Muller
Microtubule organizing centers (MTOCs) form, anchor and stabilize the polarized network of microtubules in a cell. The central MTOC is the centrosome that duplicates during the cell cycle and during mitosis assembles a bipolar spindle to capture and segregate sister chromatids. Yet, despite their importance in cell biology, the physical structure of MTOCs is poorly understood. Here we determine the molecular architecture of the core of the yeast spindle pole body (SPB) by Bayesian integrative structure modeling based on in vivo FRET, small-angle X-ray scattering (SAXS), X-ray crystallography, electron microscopy and two-hybrid analysis...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814504/osm1-facilitates-the-transfer-of-electrons-from-erv1-to-fumarate-in-the-redox-regulated-import-pathway-in-the-mitochondrial-intermembrane-space
#5
Sonya E Neal, Deepa V Dabir, Juwina Wijaya, Cennyana Boon, Carla M Koehler
Prokaryotes have aerobic and anaerobic electron acceptors for oxidative folding of periplasmic proteins. The mitochondrial intermembrane space has an analogous pathway with the oxidoreductase Mia40 and sulfhydryl oxidase Erv1, termed the MIA pathway. The aerobic electron acceptors include oxygen and cytochrome c, but an acceptor that can function under anaerobic conditions has not been identified. Here we show that the fumarate reductase Osm1, which facilitates electron transfer from fumarate to succinate, fills this gap as a new electron acceptor...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814503/transition-of-yeast-can1-transporter-to-the-inward-facing-state-unveils-an-%C3%AE-arrestin-target-sequence-promoting-its-ubiquitylation-and-endocytosis
#6
Christos Gournas, Elie Saliba, Eva-Maria Krammer, Céline Barthelemy, Martine Prévost, Bruno André
Substrate-transport-elicited endocytosis is a common control mechanism of membrane transporters avoiding excess uptake of external compounds, though poorly understood at the molecular level. In yeast, endocytosis of transporters is triggered by their ubiquitylation mediated by the Rsp5 ubiquitin-ligase, recruited by α-arrestin-family adaptors. We here report that transport-elicited ubiquitylation of the arginine transporter Can1 is promoted by transition to an inward-facing state. This conformational change unveils a region of the N-terminal cytosolic tail targeted by the Art1 α-arrestin, which is activated via the TORC1 kinase complex upon arginine uptake...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814502/selective-regulation-of-clathrin-mediated-egfr-signaling-and-endocytosis-by-phospholipase-c-and-calcium
#7
Ralph Christian Delos Santos, Stephen Bautista, Stefanie Lucarelli, Leslie N Bone, Roya M Dayam, John Abousawan, Roberto J Botelho, Costin N Antonescu
Clathrin-mediated endocytosis is a major regulator of cell surface protein internalization. Clathrin and other proteins assemble into small invaginating structures at the plasma membrane termed clathrin-coated pits (CCPs) that mediate vesicle formation. In addition, epidermal growth factor (EGF) receptor (EGFR) signaling is regulated by its accumulation within CCPs. Given the diversity of proteins regulated by clathrin-mediated endocytosis, how this process may distinctly regulate specific receptors is a key question...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814501/knockout-of-the-golgi-stacking-proteins-grasp55-and-grasp65-impairs-golgi-structure-and-function
#8
Michael E Bekier, Leibin Wang, Jie Li, Haoran Huang, Danming Tang, Xiaoyan Zhang, Yanzhuang Wang
GRASP65 and GRASP55 were originally identified as Golgi stacking proteins; however, subsequent GRASP knockdown experiments yielded inconsistent results with respect to the Golgi structure, indicating a limitation of RNAi-based depletion. In this study, we have applied the recently developed CRISPR-Cas9 technology to knock out GRASP55 and GRASP65, individually or in combination, in HeLa and HEK293 cells. We show that double knockout of GRASP proteins disperses the Golgi stack into single cisternae and tubulovesicular structures, accelerates protein trafficking, and impairs accurate glycosylation of proteins and lipids...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28814500/mono-ubiquitination-of-syntaxin-3-leads-to-retrieval-from-the-basolateral-plasma-membrane-and-facilitates-cargo-recruitment-to-exosomes
#9
Adrian J Giovannone, Elena Reales, Pallavi Bhattaram, Alberto Fraile-Ramos, Thomas Weimbs
Syntaxin 3 (Stx3), a SNARE protein located and functioning at the apical plasma membrane of epithelial cells, is required for epithelial polarity. A fraction of Stx3 is localized to late endosomes/lysosomes though how it traffics there and its function in these organelles is unknown. Here we report that Stx3 undergoes mono-ubiquitination in a conserved polybasic domain. Stx3 present at the basolateral - but not the apical - plasma membrane is rapidly endocytosed, targeted to endosomes, internalized into intraluminal vesicles (ILVs) and excreted in exosomes...
August 16, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794270/the-golgin-protein-coy1-functions-in-intra-golgi-retrograde-transport-and-interacts-with-the-cog-complex-and-golgi-snares
#10
Nadine S Anderson, Indrani Mukherjee, Christine M Bentivoglio, Charles Barlowe
Extended coiled-coil proteins of the Golgin family play prominent roles in maintaining the structure and function of the Golgi complex. Here we further investigate the Golgin protein Coy1 and document its function in retrograde transport between early Golgi compartments. Cells that lack Coy1 displayed a reduced half-life of the Och1 mannosyltransferase, an established cargo of intra-Golgi retrograde transport. Combining the coy1Δ mutation with deletions in other putative retrograde Golgins (sgm1Δ and rud3Δ) caused strong glycosylation and growth defects and reduced membrane association of the Conserved Oligomeric Golgi complex...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794269/the-fc%C3%AE%C2%B5ri-signaling-cascade-and-integrin-trafficking-converge-at-patterned-ligand-surfaces
#11
Devin L Wakefield, David Holowka, Barbara Baird
We examined the spatial targeting of early and downstream signaling mediated by the IgE receptor (FcεRI) in RBL mast cells utilizing surface-patterned 2,4 dinitrophenyl (DNP) ligands. Micron-sized features of DNP are presented as densely immobilized conjugates of bovine serum albumin (DNP-BSA) or mobile in a supported lipid bilayer (DNP-SLB). Although soluble anti-DNP IgE binds uniformly across features for both pattern types, IgE bound to FcεRI on cells shows distinctive distributions: uniform for DNP-SLB and edge-concentrated for DNP-BSA...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794268/force-induced-transcellular-tunnel-formation-in-endothelial-cells
#12
Win Pin Ng, Kevin D Webster, Caroline Stefani, Eva M Schmid, Emmanuel Lemichez, Patricia Bassereau, Daniel A Fletcher
The endothelium serves as a protective semipermeable barrier in blood vessels and lymphatic vessels. Leukocytes and pathogens can pass directly through the endothelium by opening holes in endothelial cells, known as transcellular tunnels, which are formed by contact and self-fusion of the apical and basal plasma membranes. Here we test the hypothesis that the actin cytoskeleton is the primary barrier to transcellular tunnel formation using a combination of atomic force microscopy and fluorescence microscopy of live cells...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794267/coi1-is-a-novel-assembly-factor-of-the-yeast-complex-iii-complex-iv-supercomplex
#13
Ravi K Singhal, Christine Kruse, Juliana Heidler, Valentina Strecker, Klaus Zwicker, Lea Düsterwald, Benedikt Westermann, Johannes M Herrmann, Ilka Wittig, Doron Rapaport
The yeast bc1 complex (complex III) and cytochrome oxidase (complex IV) are mosaics of core subunits encoded by the mitochondrial genome and additional nuclear-encoded proteins imported from the cytosol. Both complexes build in the mitochondrial inner membrane various supramolecular assemblies. The formation of the individual complexes and their supercomplexes depends on the activity of dedicated assembly factors. We identified a so far uncharacterized mitochondrial protein (open reading frame YDR381C-A) as an important assembly factor for complex III, complex IV, and their supercomplexes...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794266/multi-scale-tracking-reveals-scale-dependent-chromatin-dynamics-after-dna-damage
#14
Judith Miné-Hattab, Vincent Recamier, Ignacio Izeddin, Rodney Rothstein, Xavier Darzacq
The dynamic organization of genes inside the nucleus is an important determinant for their function. Using fast DNA tracking microscopy in S. cerevisiae cells and improved analysis of mean square displacements, we quantified DNA motion at time scales ranging from 10 milliseconds to minute and found that following DNA damage, DNA exhibits distinct sub-diffusive regimes. In response to double-strand breaks, chromatin is more mobile at large time scales but, surprisingly, its mobility is reduced at short time scales...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794265/reconstituted-impdh-polymers-accommodate-both-catalytically-active-and-inactive-conformations
#15
Sajitha A Anthony, Anika L Burrell, Matthew C Johnson, Krisna C Duong-Ly, Yin-Ming Kuo, Jacqueline C Simonet, Peter Michener, Andrew Andrews, Justin M Kollman, Jeffrey R Peterson
Several metabolic enzymes undergo reversible polymerization into macromolecular assemblies. The function of these assemblies is often unclear but in some cases they regulate enzyme activity and metabolic homeostasis. The guanine nucleotide biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH) forms octamers that polymerize into helical chains. In mammalian cells, IMPDH filaments can associate into micron-length assemblies. Polymerization and enzyme activity are regulated in part by binding of purine nucleotides to an allosteric regulatory domain...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794264/liquid-phase-electron-microscopy-of-molecular-drug-response-in-breast-cancer-cells-reveals-irresponsive-cell-subpopulations-related-to-lack-of-her2-homodimers
#16
Diana B Peckys, Ulrike Korf, Stefan Wiemann, Niels de Jonge
The development of drug resistance in cancer poses a major clinical problem. An example is human epidermal growth factor receptor 2 (HER2) overexpressing breast cancer often treated with anti-HER2 antibody therapies, such as trastuzumab. Since drug resistance is rooted mainly in tumor cell heterogeneity, we examined the drug effect in different subpopulations of SKBR3 breast cancer cells, and compared the results with a drug resistant cell line, HCC1954. Correlative light microscopy and liquid-phase scanning transmission electron microscopy (STEM) were used to quantitatively analyze HER2 responses upon drug binding, whereby many tens of whole cells were imaged...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794263/a-conserved-signaling-network-monitors-delivery-of-sphingolipids-to-the-plasma-membrane-in-budding-yeast
#17
Jesse Clarke, Noah Dephoure, Ira Horecka, Steven Gygi, Douglas Kellogg
In budding yeast, cell cycle progression and ribosome biogenesis are dependent upon plasma membrane growth, which ensures that events of cell growth are coordinated with each other and with the cell cycle. However, the signals that link the cell cycle and ribosome biogenesis to membrane growth are poorly understood. Here, we used proteome-wide mass spectrometry to systematically discover signals associated with membrane growth. The results suggest that membrane trafficking events required for membrane growth generate sphingolipid-dependent signals...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794262/super-resolution-microscopy-of-the-%C3%A3-carboxysome-reveals-a-homogenous-matrix
#18
Matthew J Niederhuber, Talley J Lambert, Clarence Yapp, Pamela A Silver, Jessica K Polka
Carbon fixation in cyanobacteria makes a major contribution to the global carbon cycle. The cyanobacterial carboxysome is a proteinaceous microcompartment that protects and concentrates the carbon-fixing enzyme RuBisCO in a paracrystalline lattice, making it possible for these organisms to fix CO2 from the atmosphere. The protein responsible for the organization of this lattice in beta-type carboxysomes of the freshwater cyanobacterium Synechococcus elongatus, CcmM, occurs in two isoforms thought to localize differentially within the carboxysome matrix...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28794261/neuroprotective-astrocyte-derived-insulin-igf-1-stimulate-endocytic-processing-and-extracellular-release-of-neuron-bound-a%C3%AE-oligomers
#19
Jason Pitt, Kyle C Wilcox, Vanessa Tortelli, Luan Pereira Diniz, Maira S Oliveira, Cassandra Dobbins, Xiao-Wen Yu, Sathwik Nandamuri, Flávia C A Gomes, Nadia DiNunno, Kirsten L Viola, Fernanda G De Felice, Sergio T Ferreira, William L Klein
Synaptopathy underlying memory deficits in Alzheimer's disease (AD) is increasingly thought to be instigated by toxic oligomers of the amyloid beta peptide (AβOs). Given the long latency and incomplete penetrance of AD dementia with respect to Aβ pathology, we hypothesized that factors present in the CNS may physiologically protect neurons from the deleterious impact of AβOs. Here we employed physically-separated neuron-astrocyte co-cultures to investigate potential non cell-autonomous neuroprotective factors influencing AβO toxicity...
August 9, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28768830/neurodegeneration-associated-mutant-trem2-proteins-abortively-cycle-between-the-er-and-er-golgi-intermediate-compartment
#20
Daniel W Sirkis, Renan E Aparicio, Randy Schekman
Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein expressed on microglia within the brain. Several rare mutations in TREM2 cause an early-onset form of neurodegeneration when inherited homozygously. Here we investigate how these mutations affect the intracellular transport of TREM2. We find that most pathogenic TREM2 mutant proteins fail to undergo normal maturation in the Golgi complex and show markedly reduced cell surface expression. Prior research has suggested that two such mutants are retained in the endoplasmic reticulum (ER), but we find, using a cell-free COPII vesicle budding reaction, that mutant TREM2 is exported efficiently from the ER...
August 2, 2017: Molecular Biology of the Cell
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