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Jin Chu, Domenico Praticò
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown. In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, cation independent mannose 6-phosphate receptor, sortilin-related receptor in brains of Tg2576 and controls at the ages of 3, 8, and 14 months...
January 3, 2017: Neurobiology of Aging
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
Kirsty J McMillan, Matthew Gallon, Adam P Jellett, Thomas Clairfeuille, Frances C Tilley, Ian McGough, Chris M Danson, Kate J Heesom, Kevin A Wilkinson, Brett M Collins, Peter J Cullen
The retromer complex acts as a scaffold for endosomal protein complexes that sort integral membrane proteins to various cellular destinations. The retromer complex is a heterotrimer of VPS29, VPS35, and VPS26. Two of these paralogues, VPS26A and VPS26B, are expressed in humans. Retromer dysfunction is associated with neurodegenerative disease, and recently, three VPS26A mutations (p.K93E, p.M112V, and p.K297X) were discovered to be associated with atypical parkinsonism. Here, we apply quantitative proteomics to provide a detailed description of the retromer interactome...
August 15, 2016: Journal of Cell Biology
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
Lamba Omar Sangaré, Tchilabalo Dilezitoko Alayi, Benoit Westermann, Agnes Hovasse, Fabien Sindikubwabo, Isabelle Callebaut, Elisabeth Werkmeister, Frank Lafont, Christian Slomianny, Mohamed-Ali Hakimi, Alain Van Dorsselaer, Christine Schaeffer-Reiss, Stanislas Tomavo
Membrane trafficking pathways play critical roles in Apicomplexa, a phylum of protozoan parasites that cause life-threatening diseases worldwide. Here we report the first retromer-trafficking interactome in Toxoplasma gondii. This retromer complex includes a trimer Vps35-Vps26-Vps29 core complex that serves as a hub for the endosome-like compartment and parasite-specific proteins. Conditional ablation of TgVps35 reveals that the retromer complex is crucial for the biogenesis of secretory organelles and for maintaining parasite morphology...
2016: Nature Communications
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
Jordan Follett, Andrea Bugarcic, Brett M Collins, Rohan D Teasdale
The retromer complex is a highly conserved membrane trafficking assembly composed of three proteins - Vps26, Vps29 and Vps35 - that was identified over a decade ago in Saccharomyces cerevisiae (S. cerevisiae). Initially, mammalian retromer was shown to sort transmembrane proteins from the endosome to the trans-Golgi network (TGN), though recent work has identified a critical role for retromer in multiple trafficking pathways, including recycling to the plasma membrane and regulation of cell polarity. In recent years, genetic, cellular, pharmacological and animal model studies have identified retromer and its interacting proteins as being linked to familial forms of neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's (PD)...
March 11, 2016: Current Protein & Peptide Science
Marcel Vergés
Retromer is an evolutionary conserved protein complex required for endosome-to-Golgi retrieval of receptors for lysosomal hydrolases. It is constituted by a heterotrimer encoded by the vacuolar protein sorting (VPS) gene products Vps26, Vps35, and Vps29, which selects cargo, and a dimer of phosphoinositide-binding sorting nexins, which deforms the membrane. Recent progress in the mechanism of retromer assembly and functioning has strengthened the link between sorting at the endosome and cytoskeleton dynamics...
2016: International Review of Cell and Molecular Biology
Mohd Shameel Iqbal, Asim Azhar Siddiqui, Athar Alam, Manish Goyal, Chinmoy Banerjee, Souvik Sarkar, Somnath Mazumder, Rudranil De, Shiladitya Nag, Shubhra Jyoti Saha, Uday Bandyopadhyay
Translocation of various proteins to the subcellular organelles is an essential mechanism to regulate the metabolic pathways and often vacuolar protein sorting (VPS) proteins are involved in this transportation. Plasmodium falciparum VPS29 (PfVPS29) is predicted to be a functional component in the assembly of the retromer complex; however, so far detailed characterization of PfVPS29 in its native form is not yet done. We report the successful expression and purification of tag-free recombinant PfVPS29 with a yield of 5...
April 2016: Protein Expression and Purification
Dragos Scarlet, Reinhard Ertl, Christine Aurich, Ralf Steinborn
BACKGROUND: Vertebrate evolution is accompanied by a substantial conservation of transcriptional programs with more than a third of unique orthologous genes showing constrained levels of expression. Moreover, there are genes and exons exhibiting excellent expression stability according to RNA-seq data across a panel of eighteen tissues including the ovary (Human Body Map 2.0). RESULTS: We hypothesized that orthologs of these exons would also be highly uniformly expressed across neonatal ovaries of the horse, which would render them appropriate reference genes (RGs) for normalization of reverse transcription quantitative PCR (RT-qPCR) data in this context...
2015: PloS One
Christopher Trousdale, Kyoungtae Kim
Retrograde transport from the endosome to the Golgi is mediated by a 5 protein complex known as the retromer. These five proteins (Vps5, Vps17, Vps26, Vps29, and Vps35 in yeast and SNX1/2, SNX5/6, Vps26, Vps29, and Vps35 in mammalian cells) act as a coat for vesicles budding off of the endosome, as well as perform cargo sorting at the endosome. The retromer is well conserved between yeast and mammalian systems, though variations exist within the mammalian retromer. Functionally, the retromer has been linked to prominent neurodegenerative diseases such as Alzheimer's and Parkinson's in human models as well as diabetes mellitus...
November 2015: European Journal of Cell Biology
Tamás Maruzs, Péter Lőrincz, Zsuzsanna Szatmári, Szilvia Széplaki, Zoltán Sándor, Zsolt Lakatos, Gina Puska, Gábor Juhász, Miklós Sass
The retromer is an evolutionarily conserved coat complex that consists of Vps26, Vps29, Vps35 and a heterodimer of sorting nexin (Snx) proteins in yeast. Retromer mediates the recycling of transmembrane proteins from endosomes to the trans-Golgi network, including receptors that are essential for the delivery of hydrolytic enzymes to lysosomes. Besides its function in lysosomal enzyme receptor recycling, involvement of retromer has also been proposed in a variety of vesicular trafficking events, including early steps of autophagy and endocytosis...
October 2015: Traffic
Andrea Bugarcic, Irina Vetter, Silke Chalmers, Genevieve Kinna, Brett M Collins, Rohan D Teasdale
Retromer is a trimeric complex composed of Vps26, Vps29, and Vps35 and has been shown to be involved in trafficking and sorting of transmembrane proteins within the endosome. The Vps26 paralog, Vps26B, defines a distinct retromer complex (Vps26B-retromer) in vivo and in vitro. Although endosomally associated, Vps26B-retromer does not bind the established retromer transmembrane cargo protein, cation-independent mannose 6-phosphate receptor (CI-M6PR), indicating it has a distinct role to retromer containing the Vps26A paralog...
November 2015: Cell Biology International
Atsuhito Fuse, Norihiko Furuya, Soichiro Kakuta, Aki Inose, Masumi Sato, Masato Koike, Shinji Saiki, Nobutaka Hattori
Retromer is a complex of proteins that functions in the endosome-to-Golgi retrieval cargo transport pathway. VPS35 works as the central subunit of retromer to recognize the cargos and binds with VPS29 and VPS26 via distinct domains. We show that deficiency of VPS35 or VPS29 accompanies degradation of other subunits, whereas VPS26 deficiency had no effect on VPS29 and VPS35 levels. Although VPS35 forms VPS26-VPS35 and VPS29-VPS35 sub-complexes with similar efficiency in vitro, VPS26-VPS35 was more easily degradable by the ubiquitin-proteasome-system than VPS29-VPS35...
June 4, 2015: FEBS Letters
Emil K Gustavsson, Ilaria Guella, Joanne Trinh, Chelsea Szu-Tu, Alex Rajput, Ali H Rajput, John C Steele, Martin McKeown, Beom S Jeon, Jan O Aasly, Matthew J Farrer
BACKGROUND: A pathogenic mutation (VPS35 p.D620N) within the retromer complex has been shown to segregate with late-onset Parkinson's disease (PD). Several studies have subsequently detected the mutation in patients with PD and not in controls. METHODS: Mutation screening of the coding regions of the retromer cargo recognition complex genes (VPS26A/B, VPS29, and VPS35) was carried out in patients with PD (n = 396), atypical parkinsonism (n = 229), and in 368 controls...
April 2015: Movement Disorders: Official Journal of the Movement Disorder Society
Makoto Shirakawa, Haruko Ueda, Tomoo Shimada, Takayuki Kohchi, Ikuko Hara-Nishimura
Myrosin cells, which accumulate myrosinase to produce toxic compounds when they are ruptured by herbivores, form specifically along leaf veins in Arabidopsis thaliana. However, the mechanism underlying this pattern formation is unknown. Here, we show that myrosin cell development requires the endocytosis-mediated polar localization of the auxin-efflux carrier PIN1 in leaf primordia. Defects in the endocytic/vacuolar SNAREs (syp22 and syp22 vti11) enhanced myrosin cell development. The syp22 phenotype was rescued by expressing SYP22 under the control of the PIN1 promoter...
November 2014: Plant Cell
Maravillas Mellado, Yasmina Cuartero, Ramon Brugada, Marcel Verges
BACKGROUND INFORMATION: Retromer is required for endosome-to-Golgi retrieval of the cation-independent mannose 6-phosphate receptor (CI-MPR), allowing delivery of hydrolases into lysosomes. It is constituted by a conserved heterotrimer formed by vacuolar protein sorting (Vps) gene products Vps26, Vps35 and Vps29, which is in charge of cargo selection, and a dimer of phosphoinositide-binding sorting nexins (SNXs), which has a structural role. Retromer has been implicated in sorting of additional cargo...
November 2014: Biology of the Cell
Geoffrey G Hesketh, Inmaculada Pérez-Dorado, Lauren P Jackson, Lena Wartosch, Ingmar B Schäfer, Sally R Gray, Airlie J McCoy, Oliver B Zeldin, Elspeth F Garman, Michael E Harbour, Philip R Evans, Matthew N J Seaman, J Paul Luzio, David J Owen
VARP is a Rab32/38 effector that also binds to the endosomal/lysosomal R-SNARE VAMP7. VARP binding regulates VAMP7 participation in SNARE complex formation and can therefore influence VAMP7-mediated membrane fusion events. Mutant versions of VARP that cannot bind Rab32:GTP, designed on the basis of the VARP ankyrin repeat/Rab32:GTP complex structure described here, unexpectedly retain endosomal localization, showing that VARP recruitment is not dependent on Rab32 binding. We show that recruitment of VARP to the endosomal membrane is mediated by its direct interaction with VPS29, a subunit of the retromer complex, which is involved in trafficking from endosomes to the TGN and the cell surface...
June 9, 2014: Developmental Cell
Barbara Shannon, Alexandra Soto-Ortolaza, Sruti Rayaprolu, Heather D Cannon, Catherine Labbé, Bruno A Benitez, Jiyoon Choi, Timothy Lynch, Magdalena Boczarska-Jedynak, Grzegorz Opala, Anna Krygowska-Wajs, Maria Barcikowska, Jay A Van Gerpen, Ryan J Uitti, Wolfdieter Springer, Carlos Cruchaga, Zbigniew K Wszolek, Owen A Ross
We recently showed that mutation of the VPS35 gene can cause late-onset Parkinson's disease. In the present study we sequenced 702 affected subjects from the Mayo Clinic Parkinson's disease patient-control series for the VPS29 and VPS26A/B genes. We identified only 2 rare nonsynonymous variants in the VPS26A p.K93E and VPS29 p.N72H. The results show that mutations in the genes composing the retromer cargo recognition subunit are not a common cause of Parkinson's disease.
August 2014: Neurobiology of Aging
Caroline L Freeman, Geoffrey Hesketh, Matthew N J Seaman
Retromer is a vital element of the endosomal protein sorting machinery and comprises two subcomplexes that operate together to sort membrane proteins (cargo) and tubulate membranes. Tubules are formed by a dimer of sorting nexins, a key component of which is SNX1. Cargo selection is mediated by the VPS35-VPS29-VPS26 trimer, which additionally recruits the WASH complex through VPS35 binding to the WASH complex subunit FAM21. Loss of function of the WASH complex leads to dysregulation of endosome tubulation, although it is unclear how this occurs...
May 1, 2014: Journal of Cell Science
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