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https://www.readbyqxmd.com/read/27889239/structural-mechanism-for-cargo-recognition-by-the-retromer-complex
#1
María Lucas, David C Gershlick, Ander Vidaurrazaga, Adriana L Rojas, Juan S Bonifacino, Aitor Hierro
Retromer is a multi-protein complex that recycles transmembrane cargo from endosomes to the trans-Golgi network and the plasma membrane. Defects in retromer impair various cellular processes and underlie some forms of Alzheimer's disease and Parkinson's disease. Although retromer was discovered over 15 years ago, the mechanisms for cargo recognition and recruitment to endosomes have remained elusive. Here, we present an X-ray crystallographic analysis of a four-component complex comprising the VPS26 and VPS35 subunits of retromer, the sorting nexin SNX3, and a recycling signal from the divalent cation transporter DMT1-II...
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27889227/gpcr-signaling-and-trafficking-the-long-and-short-of-it
#2
REVIEW
Nathan J Pavlos, Peter A Friedman
Emerging findings disclose unexpected components of G protein-coupled receptor (GPCR) signaling and cell biology. Select GPCRs exhibit classical signaling, that is restricted to cell membranes, as well as newly described persistent signaling that depends on internalization of the GPCR bound to β-arrestins. Termination of non-canonical endosomal signaling requires intraluminal acidification and sophisticated protein trafficking machineries. Recent studies reveal the structural determinants of the trafficking chaperones...
November 23, 2016: Trends in Endocrinology and Metabolism: TEM
https://www.readbyqxmd.com/read/27883263/cargo-selectivity-of-yeast-sorting-nexins
#3
Björn D M Bean, Michael Davey, Elizabeth Conibear
Sorting nexins are PX domain-containing proteins that bind phospholipids and often act in membrane trafficking where they help to select cargo. However, the functions and cargo specificities of many sorting nexins are unknown. Here, a high-throughput imaging screen was used to identify new sorting nexin cargo in the yeast Saccharomyces cerevisiae. Deletions of nine different sorting nexins were screened for mislocalization of a set of GFP-tagged membrane proteins found at the plasma membrane, Golgi or endosomes...
November 24, 2016: Traffic
https://www.readbyqxmd.com/read/27827364/structural-and-mechanistic-insights-into-regulation-of-the-retromer-coat-by-tbc1d5
#4
Da Jia, Jin-San Zhang, Fang Li, Jing Wang, Zhihui Deng, Mark A White, Douglas G Osborne, Christine Phillips-Krawczak, Timothy S Gomez, Haiying Li, Amika Singla, Ezra Burstein, Daniel D Billadeau, Michael K Rosen
Retromer is a membrane coat complex that is recruited to endosomes by the small GTPase Rab7 and sorting nexin 3. The timing of this interaction and consequent endosomal dynamics are thought to be regulated by the guanine nucleotide cycle of Rab7. Here we demonstrate that TBC1d5, a GTPase-activating protein (GAP) for Rab7, is a high-affinity ligand of the retromer cargo selective complex VPS26/VPS29/VPS35. The crystal structure of the TBC1d5 GAP domain bound to VPS29 and complementary biochemical and cellular data show that a loop from TBC1d5 binds to a conserved hydrophobic pocket on VPS29 opposite the VPS29-VPS35 interface...
November 9, 2016: Nature Communications
https://www.readbyqxmd.com/read/27778231/identification-of-potential-predictive-markers-of-dexamethasone-resistance-in-childhood-acute-lymphoblastic-leukemia
#5
Nasrin Dehghan-Nayeri, Mostafa Rezaei-Tavirani, Mir Davood Omrani, Ahmad Gharehbaghian, Kourosh Goudarzi Pour, Peyman Eshghi
Response to dexamethasone (DEXA), as a hallmark drug in the treatment of childhood acute lymphoblastic leukemia (ALL), is one of the pivotal prognostic factors in the prediction of outcome in ALL. Identification of predictive markers of chemoresistance is beneficial to selecting of the best therapeutic protocol with the lowest effect adverse. Hence, we aimed to find drug targets using the 2DE/MS proteomics study of a DEXA-resistant cell line (REH) as a model for poor DEXA responding patients before and after drug treatment...
October 24, 2016: Journal of Cell Communication and Signaling
https://www.readbyqxmd.com/read/27766425/reduced-expression-of-setd2-and-snx9-proteins-in-chemically-induced-mammary-tumorigenesis-in-wistar-rats-a-prognostic-histological-and-proteomic-study
#6
Ishfaq Ahmad Ganaie, Samar Husain Naqvi, Swatantra Kumar Jain, Saima Wajid
Breast cancer is a major global health concern, appealing for precise prognostic approaches. Thus, the need is to have studies focusing on the identification and recognition of preliminary events leading to the disease. The present study reports the tracing of precancerous progression and serum proteomic analysis in a breast cancer model developed as a result of 7,12-dimethylbenz[a]anthracene (DMBA) administration. Mammary gland histological changes of prime importance were examined by histopathology, and immunohistochemical analysis with Ki-67 was performed to monitor enhanced cell proliferation, right from the onset of hyperplasia till neoplasia...
October 20, 2016: Protoplasma
https://www.readbyqxmd.com/read/27761583/several-adaptor-proteins-promote-intracellular-localisation-of-the-transporter-mrp4-abcc4-in-platelets-and-haematopoietic-cells
#7
Yvonne Schaletzki, Marie-Luise Kromrey, Susanne Bröderdorf, Elke Hammer, Markus Grube, Paul Hagen, Sonja Sucic, Michael Freissmuth, Uwe Völker, Andreas Greinacher, Bernhard H Rauch, Heyo K Kroemer, Gabriele Jedlitschky
The multidrug resistance protein 4 (MRP4/ABCC4) has been identified as an important transporter for signalling molecules including cyclic nucleotides and several lipid mediators in platelets and may thus represent a novel target to interfere with platelet function. Besides its localisation in the plasma membrane, MRP4 has been also detected in the membrane of dense granules in resting platelets. In polarised cells it is localised at the basolateral or apical plasma membrane. To date, the mechanism of MRP4 trafficking has not been elucidated; protein interactions may regulate both the localisation and function of this transporter...
October 20, 2016: Thrombosis and Haemostasis
https://www.readbyqxmd.com/read/27725825/differential-gene-expression-and-protein-phosphorylation-as-factors-regulating-the-state-of-the-arabidopsis-snx1-protein-complexes-in-response-to-environmental-stimuli
#8
Tzvetina Brumbarova, Rumen Ivanov
Endosomal recycling of plasma membrane proteins contributes significantly to the regulation of cellular transport and signaling processes. Members of the Arabidopsis (Arabidopsis thaliana) SORTING NEXIN (SNX) protein family were shown to mediate the endosomal retrieval of transporter proteins in response to external challenges. Our aim is to understand the possible ways through which external stimuli influence the activity of SNX1 in the root. Several proteins are known to contribute to the function of SNX1 through direct protein-protein interaction...
2016: Frontiers in Plant Science
https://www.readbyqxmd.com/read/27649450/interaction-of-the-human-papillomavirus-e6-oncoprotein-with-sorting-nexin-27-modulates-endocytic-cargo-transport-pathways
#9
Ketaki Ganti, Paola Massimi, Joaquin Manzo-Merino, Vjekoslav Tomaić, David Pim, Martin P Playford, Marcela Lizano, Sally Roberts, Christian Kranjec, John Doorbar, Lawrence Banks
A subset of high-risk Human Papillomaviruses (HPVs) are the causative agents of a large number of human cancers, of which cervical is the most common. Two viral oncoproteins, E6 and E7, contribute directly towards the development and maintenance of malignancy. A characteristic feature of the E6 oncoproteins from cancer-causing HPV types is the presence of a PDZ binding motif (PBM) at its C-terminus, which confers interaction with cellular proteins harbouring PDZ domains. Here we show that this motif allows E6 interaction with Sorting Nexin 27 (SNX27), an essential component of endosomal recycling pathways...
September 2016: PLoS Pathogens
https://www.readbyqxmd.com/read/27646272/distinct-g-protein-coupled-receptor-recycling-pathways-allow-spatial-control-of-downstream-g-protein-signaling
#10
Shanna Lynn Bowman, Daniel John Shiwarski, Manojkumar A Puthenveedu
G protein-coupled receptors (GPCRs) are recycled via a sequence-dependent pathway that is spatially and biochemically distinct from bulk recycling. Why there are two distinct recycling pathways from the endosome is a fundamental question in cell biology. In this study, we show that the separation of these two pathways is essential for normal spatial encoding of GPCR signaling. The prototypical β-2 adrenergic receptor (B2AR) activates Gα stimulatory protein (Gαs) on the endosome exclusively in sequence-dependent recycling tubules marked by actin/sorting nexin/retromer tubular (ASRT) microdomains...
September 26, 2016: Journal of Cell Biology
https://www.readbyqxmd.com/read/27595347/a-molecular-code-for-endosomal-recycling-of-phosphorylated-cargos-by-the-snx27-retromer-complex
#11
Thomas Clairfeuille, Caroline Mas, Audrey S M Chan, Zhe Yang, Maria Tello-Lafoz, Mintu Chandra, Jocelyn Widagdo, Markus C Kerr, Blessy Paul, Isabel Mérida, Rohan D Teasdale, Nathan J Pavlos, Victor Anggono, Brett M Collins
Recycling of internalized receptors from endosomal compartments is essential for the receptors' cell-surface homeostasis. Sorting nexin 27 (SNX27) cooperates with the retromer complex in the recycling of proteins containing type I PSD95-Dlg-ZO1 (PDZ)-binding motifs. Here we define specific acidic amino acid sequences upstream of the PDZ-binding motif required for high-affinity engagement of the human SNX27 PDZ domain. However, a subset of SNX27 ligands, such as the β2 adrenergic receptor and N-methyl-D-aspartate (NMDA) receptor, lack these sequence determinants...
October 2016: Nature Structural & Molecular Biology
https://www.readbyqxmd.com/read/27566131/genome-sequencing-reveals-a-splice-donor-site-mutation-in-the-snx14-gene-associated-with-a-novel-cerebellar-cortical-degeneration-in-the-hungarian-vizsla-dog-breed
#12
Joe Fenn, Mike Boursnell, Rebekkah J Hitti, Christopher A Jenkins, Rebecca L Terry, Simon L Priestnall, Patrick J Kenny, Cathryn S Mellersh, Oliver P Forman
BACKGROUND: Cerebellar cortical degeneration (CCD) is an increasingly recognised neurodegenerative disease process affecting many dog breeds. Typical presentation consists of a progressive cerebellar ataxia, with a variable age at onset and rate of progression between different breeds. Cerebellar histopathological findings typically consist of primary Purkinje neuronal degeneration and loss, with variable secondary depletion of the granular and molecular cell layers. Causative genes have been identified associated with CCD in several breeds, allowing screening for selective breeding to reduce the prevalence of these conditions...
2016: BMC Genetics
https://www.readbyqxmd.com/read/27541017/mir-98-5p-acts-as-a-target-for-alzheimer-s-disease-by-regulating-a%C3%AE-production-through-modulating-snx6-expression
#13
Qiushi Li, Xidong Li, Li Wang, Yanhui Zhang, Long Chen
Accumulation of amyloid β-peptide (Aβ) in the brain of Alzheimer disease (AD) patients is believed to be the main pathological feature of the disease. Meanwhile, miR-98-5p dysregulation was found in AD. However, whether miR-98-5p is involved in the accumulation of Aβ in AD, the underlying molecule mechanism remains unclear. In the present study, we confirmed that miR-98-5p negatively regulated sorting nexin 6 (SNX6) expression by targeting the 3'-UTR of SNX6 mRNA. Downregulation of miR-98-5p alleviated Aβ-induced viability inhibition and decreased apoptosis in SK-N-SH and SH-SY5Y cells by upregulating SNX6 expression...
August 19, 2016: Journal of Molecular Neuroscience: MN
https://www.readbyqxmd.com/read/27345367/parkinson-s-disease-related-proteins-pink1-and-parkin-repress-mitochondrial-antigen-presentation
#14
Diana Matheoud, Ayumu Sugiura, Angélique Bellemare-Pelletier, Annie Laplante, Christiane Rondeau, Magali Chemali, Ali Fazel, John J Bergeron, Louis-Eric Trudeau, Yan Burelle, Etienne Gagnon, Heidi M McBride, Michel Desjardins
Antigen presentation is essential for establishing immune tolerance and for immune responses against infectious disease and cancer. Although antigen presentation can be mediated by autophagy, here we demonstrate a pathway for mitochondrial antigen presentation (MitAP) that relies on the generation and trafficking of mitochondrial-derived vesicles (MDVs) rather than on autophagy/mitophagy. We find that PINK1 and Parkin, two mitochondrial proteins linked to Parkinson's disease (PD), actively inhibit MDV formation and MitAP...
July 14, 2016: Cell
https://www.readbyqxmd.com/read/27336679/arf6-controls-retromer-traffic-and-intracellular-cholesterol-distribution-via-a-phosphoinositide-based-mechanism
#15
Catherine Marquer, Huasong Tian, Julie Yi, Jayson Bastien, Claudia Dall'Armi, YoungJoo Yang-Klingler, Bowen Zhou, Robin Barry Chan, Gilbert Di Paolo
Small GTPases play a critical role in membrane traffic. Among them, Arf6 mediates transport to and from the plasma membrane, as well as phosphoinositide signalling and cholesterol homeostasis. Here we delineate the molecular basis for the link between Arf6 and cholesterol homeostasis using an inducible knockout (KO) model of mouse embryonic fibroblasts (MEFs). We find that accumulation of free cholesterol in the late endosomes/lysosomes of Arf6 KO MEFs results from mistrafficking of Niemann-Pick type C protein NPC2, a cargo of the cation-independent mannose-6-phosphate receptor (CI-M6PR)...
2016: Nature Communications
https://www.readbyqxmd.com/read/27278018/sorting-nexin-9-negatively-regulates-invadopodia-formation-and-function-in-cancer-cells
#16
Nawal Bendris, Carrie J S Stearns, Carlos R Reis, Jaime Rodriguez-Canales, Hui Liu, Agnieszka W Witkiewicz, Sandra L Schmid
The ability of cancer cells to degrade the extracellular matrix and invade interstitial tissues contributes to their metastatic potential. We recently showed that overexpression of sorting nexin 9 (SNX9) leads to increased cell invasion and metastasis in animal models, which correlates with increased SNX9 protein expression in metastases from human mammary cancers. Here, we report that SNX9 expression is reduced relative to neighboring normal tissues in primary breast tumors, and progressively reduced in more aggressive stages of non-small-cell lung cancers...
July 15, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27245499/the-kynurenine-pathway-in-schizophrenia-and-bipolar-disorder
#17
REVIEW
Sophie Erhardt, Lilly Schwieler, Sophie Imbeault, Göran Engberg
The kynurenine pathway of tryptophan degradation generates several neuroactive compounds. Of those, kynurenic acid is an N-methyl-d-aspartate (NMDA) and alpha7 nicotinic receptor antagonist. The kynurenic acid hypothesis of schizophrenia is built upon the fact that kynurenic acid blocks glutamate receptors and is elevated in schizophrenia. Kynurenic acid tightly controls glutamatergic and dopaminergic neurotransmission and elevated brain levels appear related to psychotic symptoms and cognitive impairments...
January 2017: Neuropharmacology
https://www.readbyqxmd.com/read/27103185/multiple-roles-of-varp-in-endosomal-trafficking-rabs-retromer-components-and-r-snare-vamp7-meet-on-varp
#18
REVIEW
Mitsunori Fukuda
VARP (VPS9-ankyrin-repeat protein, also known as ANKRD27) was originally identified as an N-terminal VPS9 (vacuolar protein sorting 9)-domain-containing protein that possesses guanine nucleotide exchange factor (GEF) activity toward small GTPase Rab21 and contains two ankyrin repeat (ANKR) domains in its central region. A number of VARP-interacting molecules have been identified during the past five years, and considerable attention is now being directed to the multiple roles of VARP in endosomal trafficking...
July 2016: Traffic
https://www.readbyqxmd.com/read/27025878/plif-a-rapid-accurate-method-to-detect-and-quantitatively-assess-protein-lipid-interactions
#19
Laurie Ceccato, Gaëtan Chicanne, Virginie Nahoum, Véronique Pons, Bernard Payrastre, Frédérique Gaits-Iacovoni, Julien Viaud
Phosphoinositides are a type of cellular phospholipid that regulate signaling in a wide range of cellular and physiological processes through the interaction between their phosphorylated inositol head group and specific domains in various cytosolic proteins. These lipids also influence the activity of transmembrane proteins. Aberrant phosphoinositide signaling is associated with numerous diseases, including cancer, obesity, and diabetes. Thus, identifying phosphoinositide-binding partners and the aspects that define their specificity can direct drug development...
March 29, 2016: Science Signaling
https://www.readbyqxmd.com/read/27008860/actin-sorting-nexin-27-snx27-retromer-complex-mediates-rapid-parathyroid-hormone-receptor-recycling
#20
Jennifer C McGarvey, Kunhong Xiao, Shanna L Bowman, Tatyana Mamonova, Qiangmin Zhang, Alessandro Bisello, W Bruce Sneddon, Juan A Ardura, Frederic Jean-Alphonse, Jean-Pierre Vilardaga, Manojkumar A Puthenveedu, Peter A Friedman
The G protein-coupled parathyroid hormone receptor (PTHR) regulates mineral-ion homeostasis and bone remodeling. Upon parathyroid hormone (PTH) stimulation, the PTHR internalizes into early endosomes and subsequently traffics to the retromer complex, a sorting platform on early endosomes that promotes recycling of surface receptors. The C terminus of the PTHR contains a type I PDZ ligand that binds PDZ domain-containing proteins. Mass spectrometry identified sorting nexin 27 (SNX27) in isolated endosomes as a PTHR binding partner...
May 20, 2016: Journal of Biological Chemistry
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