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https://www.readbyqxmd.com/read/28544880/systems-wide-studies-uncover-commander-a-multiprotein-complex-essential-to-human-development
#1
REVIEW
Anna L Mallam, Edward M Marcotte
Recent mass spectrometry maps of the human interactome independently support the existence of a large multiprotein complex, dubbed "Commander." Broadly conserved across animals and ubiquitously expressed in nearly every human cell type examined thus far, Commander likely plays a fundamental cellular function, akin to other ubiquitous machines involved in expression, proteostasis, and trafficking. Experiments on individual subunits support roles in endosomal protein sorting, including the trafficking of Notch proteins, copper transporters, and lipoprotein receptors...
May 24, 2017: Cell Systems
https://www.readbyqxmd.com/read/28482024/vps35-in-cooperation-with-lrrk2-regulates-synaptic-vesicle-endocytosis-through-the-endosomal-pathway-in-drosophila
#2
Tsuyoshi Inoshita, Taku Arano, Yuka Hosaka, Hongrui Meng, Yujiro Umezaki, Sakiko Kosugi, Takako Morimoto, Masato Koike, Hui-Yun Chang, Yuzuru Imai, Nobutaka Hattori
Mutations of the retromer component Vps35 and endosomal kinase LRRK2 are linked to autosomal dominant forms of familial Parkinson's disease (PD). However, the physiological and pathological roles of Vps35 and LRRK2 in neuronal functions are poorly understood. Here, we demonstrated that the loss of Drosophila Vps35 (dVps35) affects synaptic vesicle recycling, dopaminergic synaptic release and sleep behavior associated with dopaminergic activity, which is rescued by the expression of wild-type dVps35 but not the PD-associated mutant dVps35 D647N...
May 8, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28477369/snx27-interactome-in-t-lymphocytes-identifies-zo-2-dynamic-redistribution-at-the-immune-synapse
#3
María Tello-Lafoz, Gonzalo Martínez-Martínez, Cristina Rodríguez-Rodríguez, Juan Pablo Albar, Morgan Huse, Severine Gharbi, Isabel Merida
T lymphocyte recognition of antigens leads to the formation of a highly organized structure termed immune synapse (IS) by analogy with the nervous synapse. Sorting nexin 27 (SNX27) controls the endosomal traffic of PDZ domain-interacting proteins, and its alteration is associated with impaired synaptic function and neurological diseases. In T lymphocytes SNX27-positive vesicles polarize to the IS, the identity of SNX27 interactors in these conditions nonetheless remains unknown. Here we used proteomics to analyze the SNX27 interactome purified from IS-forming T cells, and confirmed the conserved nature of the SNX27/WASH/retromer association in hematopoietic cells...
May 6, 2017: Traffic
https://www.readbyqxmd.com/read/28469074/sorcs2-mediated-nr2a-trafficking-regulates-motor-deficits-in-huntington-s-disease
#4
Qian Ma, Jianmin Yang, Teresa A Milner, Jean-Paul G Vonsattel, Mary Ellen Palko, Lino Tessarollo, Barbara L Hempstead
Motor dysfunction is a prominent and disabling feature of Huntington's disease (HD), but the molecular mechanisms that dictate its onset and progression are unknown. The N-methyl-D-aspartate receptor 2A (NR2A) subunit regulates motor skill development and synaptic plasticity in medium spiny neurons (MSNs) of the striatum, cells that are most severely impacted by HD. Here, we document reduced NR2A receptor subunits on the dendritic membranes and at the synapses of MSNs in zQ175 mice that model HD. We identify that SorCS2, a vacuolar protein sorting 10 protein-domain (VPS10P-domain) receptor, interacts with VPS35, a core component of retromer, thereby regulating surface trafficking of NR2A in MSNs...
May 4, 2017: JCI Insight
https://www.readbyqxmd.com/read/28450454/sortilin-and-retromer-mediate-retrograde-transport-of-glut4-in-3t3-l1-adipocytes
#5
Xiang Pan, Nava Zaarur, Maneet Singh, Peter Morin, Konstantin V Kandror
Sortilin is a multi-ligand sorting receptor responsible for the anterograde transport of lysosomal enzymes and substrates. Here, we demonstrate that sortilin is also involved in the retrograde protein traffic. In cultured 3T3-L1 adipocytes, sortilin together with retromer rescues Glut4 from the degradation in lysosomes and retrieves it to the TGN where the insulin-responsive vesicles are formed. Mechanistically, the luminal Vps10p domain of sortilin interacts with the first luminal loop of Glut4, while the cytoplasmic tail of sortilin binds to retromer...
April 27, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28449947/barcoding-of-gpcr-trafficking-and-signaling-through-the-various-trafficking-roadmaps-by-compartmentalized-signaling-networks
#6
REVIEW
Suleiman W Bahouth, Mohammed M Nooh
Proper signaling by G protein coupled receptors (GPCR) is dependent on the specific repertoire of transducing, enzymatic and regulatory kinases and phosphatases that shape its signaling output. Activation and signaling of the GPCR through its cognate G protein is impacted by G protein-coupled receptor kinase (GRK)-imprinted "barcodes" that recruit β-arrestins to regulate subsequent desensitization, biased signaling and endocytosis of the GPCR. The outcome of agonist-internalized GPCR in endosomes is also regulated by sequence motifs or "barcodes" within the GPCR that mediate its recycling to the plasma membrane or retention and eventual degradation as well as its subsequent signaling in endosomes...
April 24, 2017: Cellular Signalling
https://www.readbyqxmd.com/read/28442266/cln5-is-cleaved-by-members-of-the-spp-sppl-family-to-produce-a-mature-soluble-protein
#7
Felix Jules, Etienne Sauvageau, Karine Dumaresq-Doiron, Javier Mazzaferri, Martina Haug-Kröper, Regina Fluhrer, Santiago Costantino, Stephane Lefrancois
The Neuronal ceroid lipofuscinoses (NCLs) are a group of recessive disorders of childhood with overlapping symptoms including vision loss, ataxia, cognitive regression and premature death. 14 different genes have been linked to NCLs (CLN1-CLN14), but the functions of the proteins encoded by the majority of these genes have not been fully elucidated. Mutations in the CLN5 gene are responsible for the Finnish variant late-infantile form of NCL (Finnish vLINCL). CLN5 is translated as a 407 amino acid transmembrane domain containing protein that is heavily glycosylated, and subsequently cleaved into a mature soluble protein...
April 22, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28399880/quantitative-proteomic-analysis-of-parkin-substrates-in-drosophila-neurons
#8
Aitor Martinez, Benoit Lectez, Juanma Ramirez, Oliver Popp, James D Sutherland, Sylvie Urbé, Gunnar Dittmar, Michael J Clague, Ugo Mayor
BACKGROUND: Parkin (PARK2) is an E3 ubiquitin ligase that is commonly mutated in Familial Parkinson's Disease (PD). In cell culture models, Parkin is recruited to acutely depolarised mitochondria by PINK1. PINK1 activates Parkin activity leading to ubiquitination of multiple proteins, which in turn promotes clearance of mitochondria by mitophagy. Many substrates have been identified using cell culture models in combination with depolarising drugs or proteasome inhibitors, but not in more physiological settings...
April 11, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28399507/the-emerging-role-of-retromer-in-neuroprotection
#9
REVIEW
Kirsty J McMillan, Hendrick C Korswagen, Peter J Cullen
Efficient sorting and transportation of integral membrane proteins, such as ion channels, nutrient transporters, signalling receptors, cell-cell and cell-matrix adhesion molecules is essential for the function of cellular organelles and hence organism development and physiology. Retromer is a master controller of integral membrane protein sorting and transport through one of the major sorting station within eukaryotic cells, the endosomal network. Subtle de-regulation of retromer is an emerging theme in the pathoetiology of Parkinson's disease...
April 8, 2017: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/28384478/the-retromer-supports-ampa-receptor-trafficking-during-ltp
#10
Paul Temkin, Wade Morishita, Debanjan Goswami, Kristin Arendt, Lu Chen, Robert Malenka
Alterations in the function of the retromer, a multisubunit protein complex that plays a specialized role in endosomal sorting, have been linked to Alzheimer's and Parkinson's diseases, yet little is known about the retromer's role in the mature brain. Using in vivo knockdown of the critical retromer component VPS35, we demonstrate a specific role for this endosomal sorting complex in the trafficking of AMPA receptors during NMDA-receptor-dependent LTP at mature hippocampal synapses. The impairment of LTP due to VPS35 knockdown was mechanistically independent of any role of the retromer in the production of Aβ from APP...
April 5, 2017: Neuron
https://www.readbyqxmd.com/read/28362258/a-cdc25-family-protein-phosphatase-gates-cargo-recognition-by-the-vps26-retromer-subunit
#11
Tie-Zhong Cui, Tabitha A Peterson, Christopher G Burd
We describe a regulatory mechanism that controls the activity of retromer, an evolutionarily conserved sorting device that orchestrates cargo export from the endosome. A spontaneously arising mutation that activates the yeast (Saccharomyces cerevisiae) CDC25 family phosphatase, Mih1, results in accelerated turnover of a subset of endocytosed plasma membrane proteins due to deficient sorting into a retromer-mediated recycling pathway. Mih1 directly modulates the phosphorylation state of the Vps26 retromer subunit; mutations engineered to mimic these states modulate the binding affinities of Vps26 for a retromer cargo, resulting in corresponding changes in cargo sorting at the endosome...
March 31, 2017: ELife
https://www.readbyqxmd.com/read/28353286/interaction-of-lrrk2-and-%C3%AE-synuclein-in-parkinson-s-disease
#12
João Paulo Lima Daher
Parkinson's disease (PD) is a progressively debilitating neurodegenerative syndrome. It is best described as a movement disorder characterized by motor dysfunctions, progressive degeneration of dopaminergic neurons of the substantia nigra pars compacta, and abnormal intraneuronal protein aggregates, named Lewy bodies and Lewy neurites. Nevertheless, knowledge of the molecular events leading to this pathophysiology is incomplete. To date, only mutations in the α-synuclein and LRRK2-encoding genes have been associated with typical findings of clinical and pathologic PD...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28252385/chlamydia-interfere-with-an-interaction-between-the-mannose-6-phosphate-receptor-and-sorting-nexins-to-counteract-host-restriction
#13
Cherilyn A Elwell, Nadine Czudnochowski, John von Dollen, Jeffrey R Johnson, Rachel Nakagawa, Kathleen Mirrashidi, Nevan J Krogan, Joanne N Engel, Oren S Rosenberg
Chlamydia trachomatis is an obligate intracellular pathogen that resides in a membrane-bound compartment, the inclusion. The bacteria secrete a unique class of proteins, Incs, which insert into the inclusion membrane and modulate the host-bacterium interface. We previously reported that IncE binds specifically to the Sorting Nexin 5 Phox domain (SNX5-PX) and disrupts retromer trafficking. Here, we present the crystal structure of the SNX5-PX:IncE complex, showing IncE bound to a unique and highly conserved hydrophobic groove on SNX5...
March 2, 2017: ELife
https://www.readbyqxmd.com/read/28222538/vps35-the-retromer-complex-and-parkinson-s-disease
#14
Erin T Williams, Xi Chen, Darren J Moore
Mutations in the vacuolar protein sorting 35 ortholog (VPS35) gene encoding a core component of the retromer complex, have recently emerged as a new cause of late-onset, autosomal dominant familial Parkinson's disease (PD). A single missense mutation, AspD620Asn (D620N), has so far been unambiguously identified to cause PD in multiple individuals and families worldwide. The exact molecular mechanism(s) by which VPS35 mutations induce progressive neurodegeneration in PD are not yet known. Understanding these mechanisms, as well as the perturbed cellular pathways downstream of mutant VPS35, is important for the development of appropriate therapeutic strategies...
February 8, 2017: Journal of Parkinson's Disease
https://www.readbyqxmd.com/read/28179995/caspase-mediated-proteolysis-of-the-sorting-nexin-2-disrupts-retromer-assembly-and-potentiates-met-hepatocyte-growth-factor-receptor-signaling
#15
Catherine M Duclos, Audrey Champagne, Julie C Carrier, Caroline Saucier, Christine L Lavoie, Jean-Bernard Denault
The unfolding of apoptosis involves the cleavage of hundreds of proteins by the caspase family of cysteinyl peptidases. Among those substrates are proteins involved in intracellular vesicle trafficking with a net outcome of shutting down the crucial processes governing protein transport to organelles and to the plasma membrane. However, because of the intertwining of receptor trafficking and signaling, cleavage of specific proteins may lead to unintended consequences. Here we show that in apoptosis, sorting nexin 1 and 2 (SNX1 and SNX2), two proteins involved in endosomal sorting, are cleaved by initiator caspases and also by executioner caspase-6 in the case of SNX2...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28134614/ablation-of-snx6-leads-to-defects-in-synaptic-function-of-ca1-pyramidal-neurons-and-spatial-memory
#16
Yang Niu, Zhonghua Dai, Wenxue Liu, Cheng Zhang, Yanrui Yang, Zhenzhen Guo, Xiaoyu Li, Chenchang Xu, Xiahe Huang, Yingchun Wang, Yun S Shi, Jia-Jia Liu
SNX6 is a ubiquitously expressed PX-BAR protein that plays important roles in retromer-mediated retrograde vesicular transport from endosomes. Here we report that CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory, accompanied with loss of spines from distal dendrites of hippocampal CA1 pyramidal cells. SNX6 interacts with Homer1b/c, a postsynaptic scaffold protein crucial for the synaptic distribution of other postsynaptic density (PSD) proteins and structural integrity of dendritic spines...
January 30, 2017: ELife
https://www.readbyqxmd.com/read/28131823/in-situ-peroxidase-labeling-and-mass-spectrometry-connects-alpha-synuclein-directly-to-endocytic-trafficking-and-mrna-metabolism-in-neurons
#17
Chee Yeun Chung, Vikram Khurana, Song Yi, Nidhi Sahni, Ken H Loh, Pavan K Auluck, Valeriya Baru, Namrata D Udeshi, Yelena Freyzon, Steven A Carr, David E Hill, Marc Vidal, Alice Y Ting, Susan Lindquist
Synucleinopathies, including Parkinson's disease (PD), are associated with the misfolding and mistrafficking of alpha-synuclein (α-syn). Here, using an ascorbate peroxidase (APEX)-based labeling method combined with mass spectrometry, we defined a network of proteins in the immediate vicinity of α-syn in living neurons to shed light on α-syn function. This approach identified 225 proteins, including synaptic proteins, proteins involved in endocytic vesicle trafficking, the retromer complex, phosphatases and mRNA binding proteins...
February 22, 2017: Cell Systems
https://www.readbyqxmd.com/read/28129035/where-no-ras-has-gone-before-vps35-steers-n-ras-through-the-cytosol
#18
Mo Zhou, Mark R Philips
Ras is the best-studied member of the superfamily of small GTPases because of its role in cancer. Ras proteins transmit signals for proliferation, differentiation and survival. Three RAS genes encode 4 isoforms. All Ras isoforms have long been considered membrane bound, a localization required for function. Our recent study revealed that N-Ras differs from all other isoforms in being largely cytosolic even following modification with a prenyl lipid. Endogenous, cytosolic N-Ras chromatographed in both high and low molecular weight pools, a pattern that required prenylation, suggesting prenyl-dependent interaction with other proteins...
January 27, 2017: Small GTPases
https://www.readbyqxmd.com/read/28115417/the-parkinson-s-disease-linked-protein-tmem230-is-required-for-rab8a-mediated-secretory-vesicle-trafficking-and-retromer-trafficking
#19
Myung Jong Kim, Han-Xiang Deng, Yvette C Wong, Teepu Siddique, Dimitri Krainc
TMEM230 is a newly identified Parkinson's disease (PD) gene encoding a transmembrane protein whose cellular and pathogenic roles remain largely unknown. Here, we demonstrate that loss of TMEM230 disrupts retromer cargo CI-M6PR (cation-independent mannose 6-phosphate receptor) trafficking and autophagic cargo degradation rates. TMEM230 depletion further inhibits extracellular secretion of the autophagic cargo p62 and immature lysosomal hydrolases in Golgi-derived vesicles leading to their intracellular accumulation, and is specifically mediated by loss of the small GTPase Rab8a...
February 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28110103/the-retromer-complex-system-in-a-transgenic-mouse-model-of-ad-influence-of-age
#20
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
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