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Santanu Das
GTP hydrolysis is indispensable to keep a living cell healthy. Nature has evolved so many enzymes to enhance the slow GTP hydrolysis. Rab GTPases are evolved to regulate vesicle trafficking. GTPase activating proteins (GAPs) accelerates their intrinsic slow GTP hydrolysis in order to maintain the sustainability between cellular events. Any malfunction/interference in this hydrolysis disrupts normal cellular events and causes severe diseases. In this study, GTP hydrolysis mechanism of Rab33B catalyzed by TBC-domain GAP protein Gyp1p has been decoded using extensive ab initio QM/MM metadynamics simulations...
October 12, 2017: Molecular Informatics
Constantin N Takacs, Ursula Andreo, Viet Loan Dao Thi, Xianfang Wu, Caroline E Gleason, Michelle S Itano, Gabriella S Spitz-Becker, Rachel L Belote, Brenna R Hedin, Margaret A Scull, Charles M Rice, Sanford M Simon
Secretory cells produce diverse cargoes, yet how they regulate concomitant secretory traffic remains insufficiently explored. Rab GTPases control intracellular vesicular transport. To map secretion pathways, we generated a library of lentivirus-expressed dominant-negative Rab mutants and used it in a large-scale screen to identify regulators of hepatic lipoprotein secretion. We identified several candidate pathways, including those mediated by Rab11 and Rab8. Surprisingly, inhibition of Rab1b, the major regulator of transport from the endoplasmic reticulum to the Golgi, differently affected the secretion of the very-low-density lipoprotein components ApoE and ApoB100, despite their final association on mature secreted lipoprotein particles...
October 10, 2017: Cell Reports
E L Kavanagh, S Lindsay, M Halasz, L C Gubbins, K Weiner-Gorzel, M H Z Guang, A McGoldrick, E Collins, M Henry, A Blanco-Fernández, P O' Gorman, P Fitzpatrick, M J Higgins, P Dowling, A McCann
Triple negative breast cancer (TNBC) is an aggressive subtype with relatively poor clinical outcomes and limited treatment options. Chemotherapy, while killing cancer cells, can result in the generation of highly chemoresistant therapeutic induced senescent (TIS) cells that potentially form stem cell niches resulting in metastases. Intriguingly, senescent cells release significantly more extracellular vesicles (EVs) than non-senescent cells. Our aim was to profile EVs harvested from TIS TNBC cells compared with control cells to identify a potential mechanism by which TIS TNBC cells maintain survival in the face of chemotherapy...
October 9, 2017: Oncogenesis
María C Legaria, Raquel Rollet, Ana Di Martino, Liliana Castello, Claudia Barberis, María A Rossetti, María C Guardati, Liliana Fernández Canigia, Graciela Carloni, Mirta Litterio, Marta Rocchi, Eduardo G Anchart, Fernando M Trejo, Jessica Minnaard, Diana Klajn, Silvia C Predari
The best laboratory diagnostic approach to detect Clostridioides [Clostridium] difficile infection (CDI) is a subject of ongoing debate. With the aim of evaluating four laboratory diagnostic methods, 250 unformed stools from patients with suspected CDI submitted to nine medical center laboratories from November 2010 to December 2011, were studied using: (1) an immunochromatographic rapid assay test that combines the qualitative determination of glutamate dehydrogenase (GDH) plus toxins A and B (QAB), the CDIFF QUIK CHEK COMPLETE assay; (2) an enzyme immunoassay for qualitative determination of toxins A and B, the RIDASCREEN™ C...
October 5, 2017: Revista Argentina de Microbiología
Chenyin Wang, Valeria Saar, Ka Lai Leung, Liang Chen, Garry Wong
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of extracellular amyloid plaques consisting of Amyloid-β peptide (Aβ) aggregates and neurofibrillary tangles formed by aggregation of hyperphosphorylated microtubule-associated protein tau. We generated a novel invertebrate model of AD by crossing Aβ1-42 (strain CL2355) with either pro-aggregating tau (strain BR5270) or anti-aggregating tau (strain BR5271) pan-neuronal expressing transgenic Caenorhabditis elegans...
October 2, 2017: Neurobiology of Disease
Anne Combedazou, Stéphanie Gayral, Nathalie Colombié, Anne Fougerat, Muriel Laffargue, Damien Ramel
Collective cell migration is a critical mechanism involved in cell movement during various physiological and pathological processes such as angiogenesis and metastasis formation. During collective movement, cells remain functionally connected and can coordinate individual cell behaviors to ensure efficient migration. A cell-cell communication process ensures this complex coordination. Although the mechanisms regulating cell-cell communication remain unclear, recent findings indicate that it is based on acto-myosin cytoskeleton tension transmission from cell to cell through adherens junctions...
October 5, 2017: Small GTPases
Nunzia Di Maio, Rosario Vicidomini, Alberto Angrisani, Valentina Belli, Maria Furia, Mimmo Turano
Dyskerin is an essential, conserved, multifunctional protein found in the nucleolus, whose loss of function causes the rare genetic diseases X-linked dyskeratosis congenita and Hoyeraal-Hreidarsson syndrome. To further investigate the wide range of dyskerin's biological roles, we set up stable cell lines able to trigger inducible protein knockdown and allow a detailed analysis of the cascade of events occurring within a short time frame. We report that dyskerin depletion quickly induces cytoskeleton remodeling and significant alterations in endocytic Ras-related protein Rab-5A/Rab11 trafficking...
October 2017: FEBS Open Bio
Matthias Kotzsch, Thomas Kirchner, Susanne Soelch, Sonja Schäfer, Katrin Friedrich, Gustavo Baretton, Viktor Magdolen, Thomas Luther
Dysregulated expression of rab31, a member of the large Rab protein family of the Ras superfamily of small GTPases, has been observed in several types of cancer, including breast cancer. Rab31, depending on its expression level, may regulate the switch between an invasive versus proliferative phenotype of breast cancer cells in vitro. Moreover, gene expression of rab31 is induced by the C-terminal subunit of mucin-1 (MUC1-C) and estrogen receptors (ER). To gain further insights into the clinical relevance of rab31 and mucin-1 expression in breast cancer, we analyzed the relation between rab31 and mucin-1 (CA15-3) antigen levels in detergent tissue extracts of ER-positive (ER+) tumors and clinicopathological parameters as well as patients' prognosis...
2017: American Journal of Cancer Research
Hua Yuan, Saralin Davis, Susan Ferro-Novick, Peter Novick
Ypt1 and Sec4 are essential Rab GTPases that control the early and late stages of the yeast secretory pathway, respectively. A chimera consisting of Ypt1 with the switch I domain of Sec4, Ypt1-SW1(Sec4), is efficiently activated in vitro by the Sec4 exchange factor, Sec2. This should lead to its ectopic activation in vivo and thereby disrupt membrane traffic. Nonetheless early studies found that yeast expressing Ypt1-SW1(Sec4) as the sole copy of YPT1 exhibit no growth defect. To resolve this conundrum, we have analyzed yeast expressing various levels of Ypt1-SW1(Sec4) We show that even normal expression of Ypt1-SW1(Sec4) leads to kinetic transport defects at a late stage of the pathway, with secretory vesicles accumulating near exocytic sites...
September 25, 2017: Proceedings of the National Academy of Sciences of the United States of America
Rashid Mehmood, Naveed Iqbal, Abdullah Tahir, M Mohsin Riaz, Rab Nawaz
Visual tracking and 3D representation of guidewire in fluoroscopic image sequence for beating heart image guided interventions is very challenging task. The degraded image quality due to low dose fluoroscopy further complicates the problem. In this paper a robust guidewire tracking is proposed for mean shift algorithm using integrated colour, texture and depth features. The target colour, texture and depth features are encoded into gray level intensity histogram, filtered local binary pattern histogram and filtered local depth pattern histograms respectively...
2017: Advances in Experimental Medicine and Biology
Laura S Schmidt, W Marston Linehan
Germline mutations in the novel tumor suppressor gene FLCN are responsible for the autosomal dominant inherited disorder Birt-Hogg-Dubé (BHD) syndrome that predisposes to fibrofolliculomas, lung cysts and spontaneous pneumothorax, and an increased risk for developing kidney tumors. Although the encoded protein, folliculin (FLCN), has no sequence homology to known functional domains, x-ray crystallographic studies have shown that the C-terminus of FLCN has structural similarity to DENN (differentially expressed in normal cells and neoplasia) domain proteins that act as guanine nucleotide exchange factors (GEFs) for small Rab GTPases...
September 29, 2017: Gene
Sisi Wang, Chunhong Hu, Fang Wu, Shasha He
Rab25, a small GTPase belongs to the Rab protein family, has a pivotal role in cancer pathophysiology. Rab25 governs cell-surface receptors recycling and cellular signaling pathways activation, allowing it to control a diverse range of cellular functions, including cell proliferation, cell motility and cell death. Aberrant expression of Rab25 was linked to cancer development. Majority of research findings revealed that Rab25 is an oncogene. Elevated expression of Rab25 was correlated with poor prognosis and aggressiveness of renal, lung, breast, ovarian and other cancers...
September 8, 2017: Oncotarget
Donghyuk Shin, Wooju Na, Ji-Hyung Lee, Gyuhee Kim, Jiseok Baek, Seok Hee Park, Cheol Yong Choi, Sangho Lee
Rab GTPases, which are involved in intracellular trafficking pathways, have recently been reported to be ubiquitinated. However, the functions of ubiquitinated Rab proteins remain unexplored. Here we show that Rab5 is monoubiquitinated on K116, K140, and K165. Upon co-transfection with ubiquitin, Rab5 exhibited abnormalities in endosomal localization and EGF-induced EGF receptor degradation. Rab5 K140R and K165R mutants restored these abnormalities, whereas K116R did not. We derived structural models of individual monoubiquitinated Rab5 proteins (mUbRab5s) by solution scattering and observed different conformational flexibilities in a site-specific manner...
October 2, 2017: ELife
Ilaria Piccini, Edda Fehrmann, Stefan Frank, Frank U Müller, Boris Greber, Guiscard Seebohm
The fight-or-flight response (FFR), a physiological acute stress reaction, involves positive chronotropic and inotropic effects on heart muscle cells mediated through β-adrenoceptor activation. Increased systolic calcium is required to enable stronger heart contractions whereas elevated potassium currents are to limit the duration of the action potentials and prevent arrhythmia. The latter effect is accomplished by an increased functional activity of the Kv7.1 channel encoded by KCNQ1. Current knowledge, however, does not sufficiently explain the full extent of rapid Kv7...
2017: Frontiers in Physiology
Aleksandra Kaźmierczak, Damian Kusy, Sanna P Niinivehmas, Joanna Gmach, Łukasz Joachimiak, Olli T Pentikäinen, Edyta Gendaszewska-Darmach, Katarzyna M Blazewska
Members of the Rab GTPase family are master regulators of vesicle trafficking. When disregulated, they are associated with a number of pathological states. The inhibition of RGGT, an enzyme responsible for post-translational geranylgeranylation of Rab GTPases represents one way to control the activity of these proteins. Since the number of molecules modulating RGGT is limited, we combined molecular modeling with biological assays to ascertain how modifications of phosphonocarboxylates, the first reported RGGT inhibitors, rationally improve understanding of their structure-activity relationship...
September 27, 2017: Journal of Medicinal Chemistry
Minke A E Rab, Aafke Meerveld-Eggink, Heleen van Velzen-Blad, Douwe van Loon, Ger T Rijkers, Okke de Weerdt
The effect of splenectomy on the incidence of infections and thromboembolisms has been investigated thoroughly. Nevertheless, the long-term effects of splenectomy on immunological profile and circulating blood counts have not been described before. To study such long-term effects, we analysed several parameters in splenectomised trauma patients and compared the results of this group ("otherwise healthy patients") to patients with a specific underlying disease. We measured platelet count, leukocytes and differential, lymphocyte subsets, serum levels of immunoglobulins, and complement pathways in 113 patients...
September 26, 2017: International Journal of Hematology
Samual C Allgood, Barbara P Romero Dueñas, Rebecca R Noll, Colleen Pike, Sean Lein, M Ramona Neunuebel
The facultative intracellular bacterium Legionella pneumophila proliferates within amoebae and human alveolar macrophages, and it is the causative agent of Legionnaires' disease, a life-threatening pneumonia. Within host cells, L. pneumophila establishes a replicative haven by delivering numerous effector proteins into the host cytosol, many of which target membrane trafficking by manipulating the function of Rab GTPases. The Legionella effector AnkX is a phosphocholine transferase that covalently modifies host Rab1 and Rab35...
2017: Frontiers in Cellular and Infection Microbiology
Shreya Mitra, Jeffrey E Montgomery, Matthew J Kolar, Gang Li, Kang J Jeong, Bo Peng, Gregory L Verdine, Gordon B Mills, Raymond E Moellering
Recent evidence has established a role for the small GTPase RAB25, as well as related effector proteins, in enacting both pro-oncogenic and anti-oncogenic phenotypes in specific cellular contexts. Here we report the development of all-hydrocarbon stabilized peptides derived from the RAB-binding FIP-family of proteins to target RAB25. Relative to unmodified peptides, optimized stapled peptides exhibit increased structural stability, binding affinity, cell permeability, and inhibition of RAB25:FIP complex formation...
September 22, 2017: Nature Communications
Motoki Inoshita, Joji Mima
Membrane tethering is a fundamental process essential for compartmental specificity of intracellular membrane trafficking in eukaryotic cells. Rab-family small GTPases and specific sets of Rab-interacting effector proteins, including coiled-coil tethering proteins and multisubunit tethering complexes, have been reported to be responsible for membrane tethering. However, whether and how these key components directly and specifically tether subcellular membranes still remains enigmatic. Using chemically defined proteoliposomal systems reconstituted with purified human Rab proteins and synthetic liposomal membranes to study the molecular basis of membrane tethering, we established here that Rab-family GTPases have a highly conserved function to directly mediate membrane tethering, even in the absence of any types of Rab effectors such as the so-called tethering proteins...
September 22, 2017: Journal of Biological Chemistry
L D Barlow, J B Dacks
Plant cells show many signs of a unique evolutionary history. This is seen in the system of intracellular organelles and vesicle transport pathways plants use to traffic molecular cargo. Bioinformatic and cell biological work in this area is beginning to tackle the question of how plant cells have evolved, and what this tells us about the evolution of other eukaryotes. Key protein families with membrane trafficking function, including Rabs, SNAREs, vesicle coat proteins, and ArfGAPs, show patterns of evolution that indicate both specialization and conservation in plants...
September 19, 2017: Seminars in Cell & Developmental Biology
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