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https://www.readbyqxmd.com/read/27909247/integration-of-transmembrane-domains-is-regulated-by-their-downstream-sequences
#1
Tina Junne, Martin Spiess
The Sec61 translocon catalyzes translocation of proteins into the endoplasmic reticulum and the lateral integration of transmembrane segments into the lipid bilayer. Integration is mediated by the hydrophobicity of a polypeptide segment consistent with thermodynamic equilibration between the translocon and the lipid membrane. Integration efficiency of a generic series of increasingly hydrophobic sequences (H-segments) was found to diverge significantly in different reporter constructs as a function of the ∼100 residues carboxyterminal of the H-segments...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27821549/mycolactone-subverts-immunity-by-selectively-blocking-the-sec61-translocon
#2
Ludivine Baron, Anja Onerva Paatero, Jean-David Morel, Francis Impens, Laure Guenin-Macé, Sarah Saint-Auret, Nicolas Blanchard, Rabea Dillmann, Fatoumata Niang, Sandra Pellegrini, Jack Taunton, Ville O Paavilainen, Caroline Demangel
Mycolactone, an immunosuppressive macrolide released by the human pathogen Mycobacterium ulcerans, was previously shown to impair Sec61-dependent protein translocation, but the underlying molecular mechanism was not identified. In this study, we show that mycolactone directly targets the α subunit of the Sec61 translocon to block the production of secreted and integral membrane proteins with high potency. We identify a single-amino acid mutation conferring resistance to mycolactone, which localizes its interaction site near the lumenal plug of Sec61α...
November 7, 2016: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/27582497/the-charcot-marie-tooth-disease-protein-litaf-is-a-zinc-binding-monotopic-membrane-protein
#3
Wenxia Qin, Lydia Wunderley, Anne L Barrett, Stephen High, Philip G Woodman
LITAF LPS-INDUCED TNF-ACTIVATING FACTOR IS AN ENDOSOME-ASSOCIATED INTEGRAL MEMBRANE PROTEIN IMPORTANT FOR MULTIVESICULAR BODY SORTING SEVERAL MUTATIONS IN LITAF CAUSE AUTOSOMAL DOMINANT CHARCOT MARIE TOOTH DISEASE TYPE 1C CMT1C THESE MUTATIONS MAP TO A HIGHLY CONSERVED C-TERMINAL REGION, TERMED THE LITAF DOMAIN, WHICH INCLUDES A 22 RESIDUE HYDROPHOBIC SEQUENCE AND FLANKING CYSTEINE-RICH REGIONS THAT CONTAIN PEPTIDE MOTIFS FOUND IN ZINC FINGERS ALTHOUGH THE LITAF DOMAIN IS THOUGHT TO BE RESPONSIBLE FOR MEMBRANE INTEGRATION, THE MEMBRANE TOPOLOGY OF LITAF HAS NOT BEEN ESTABLISHED HERE WE HAVE INVESTIGATED WHETHER LITAF IS A TAIL-ANCHORED MEMBRANE SPANNING PROTEIN OR MONOTOPIC MEMBRANE PROTEIN WHEN TRANSLATED IN VITRO, LITAF INTEGRATES POORLY INTO ER-DERIVED MICROSOMES COMPARED TO SEC61: B: , A BONA FIDE TAIL-ANCHORED PROTEIN FURTHERMORE, INTRODUCTION OF N-LINKED GLYCOSYLATION REPORTERS SHOWS THAT NEITHER THE N-TERMINAL OR C-TERMINAL DOMAINS OF LITAF TRANSLOCATE INTO THE ER LUMEN EXPRESSION IN CELLS OF A LITAF CONSTRUCT CONTAINING C-TERMINAL GLYCOSYLATION SITES CONFIRMS THAT LITAF IS NOT A TAIL-ANCHORED PROTEIN IN CELLS FINALLY, AN IMMUNOFLUORESCENCE-BASED LATENCY ASSAY SHOWED THAT BOTH THE N- AND C-TERMINI OF LITAF ARE EXPOSED TO THE CYTOPLASM RECOMBINANT LITAF CONTAINS 1 MOL/MOL ZINC, WHILST MUTATION OF PREDICTED ZINC-BINDING RESIDUES DISRUPTS LITAF MEMBRANE ASSOCIATION HENCE, WE CONCLUDE THAT LITAF IS A MONOTOPIC MEMBRANE PROTEIN WHOSE MEMBRANE INTEGRATION IS STABILISED BY A ZINC-FINGER THE RELATED HUMAN PROTEIN, CDIP1 CELL DEATH INVOLVED P53 TARGET 1, DISPLAYED IDENTICAL MEMBRANE TOPOLOGY, SUGGESTING THAT THIS MODE OF MEMBRANE INTEGRATION IS CONSERVED IN LITAF FAMILY PROTEINS...
August 31, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27435098/membrane-protein-insertion-and-assembly-by-the-bacterial-holo-translocon-secyeg-secdf-yajc-yidc
#4
Joanna Komar, Sara Alvira, Ryan J Schulze, Remy Martin, Jelger A Lycklama A Nijeholt, Sarah C Lee, Tim R Dafforn, Gabriele Deckers-Hebestreit, Imre Berger, Christiane Schaffitzel, Ian Collinson
Protein secretion and membrane insertion occur through the ubiquitous Sec machinery. In this system, insertion involves the targeting of translating ribosomes via the signal recognition particle and its cognate receptor to the SecY (bacteria and archaea)/Sec61 (eukaryotes) translocon. A common mechanism then guides nascent transmembrane helices (TMHs) through the Sec complex, mediated by associated membrane insertion factors. In bacteria, the membrane protein 'insertase' YidC ushers TMHs through a lateral gate of SecY to the bilayer...
October 1, 2016: Biochemical Journal
https://www.readbyqxmd.com/read/27392076/heterozygous-loss-of-function-sec61a1-mutations-cause-autosomal-dominant-tubulo-interstitial-and-glomerulocystic-kidney-disease-with-anemia
#5
Nikhita Ajit Bolar, Christelle Golzio, Martina Živná, Gaëlle Hayot, Christine Van Hemelrijk, Dorien Schepers, Geert Vandeweyer, Alexander Hoischen, Jeroen R Huyghe, Ann Raes, Erve Matthys, Emiel Sys, Myriam Azou, Marie-Claire Gubler, Marleen Praet, Guy Van Camp, Kelsey McFadden, Igor Pediaditakis, Anna Přistoupilová, Kateřina Hodaňová, Petr Vyleťal, Hana Hartmannová, Viktor Stránecký, Helena Hůlková, Veronika Barešová, Ivana Jedličková, Jana Sovová, Aleš Hnízda, Kendrah Kidd, Anthony J Bleyer, Richard S Spong, Johan Vande Walle, Geert Mortier, Han Brunner, Lut Van Laer, Stanislav Kmoch, Nicholas Katsanis, Bart L Loeys
Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively...
July 7, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27373685/organization-of-the-native-ribosome-translocon-complex-at-the-mammalian-endoplasmic-reticulum-membrane
#6
REVIEW
Stefan Pfeffer, Johanna Dudek, Richard Zimmermann, Friedrich Förster
BACKGROUND: In eukaryotic cells, many proteins have to be transported across or inserted into the endoplasmic reticulum membrane during their biogenesis on the ribosome. This process is facilitated by the protein translocon, a highly dynamic multi-subunit membrane protein complex. SCOPE OF REVIEW: The aim of this review is to summarize the current structural knowledge about protein translocon components in mammals. MAJOR CONCLUSIONS: Various structural biology approaches have been used in synergy to characterize the translocon in recent years...
October 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/27203376/apratoxin-kills-cells-by-direct-blockade-of-the-sec61-protein-translocation-channel
#7
Anja O Paatero, Juho Kellosalo, Bryan M Dunyak, Jehad Almaliti, Jason E Gestwicki, William H Gerwick, Jack Taunton, Ville O Paavilainen
Apratoxin A is a cytotoxic natural product that prevents the biogenesis of secretory and membrane proteins. Biochemically, apratoxin A inhibits cotranslational translocation into the ER, but its cellular target and mechanism of action have remained controversial. Here, we demonstrate that apratoxin A prevents protein translocation by directly targeting Sec61α, the central subunit of the protein translocation channel. Mutagenesis and competitive photo-crosslinking studies indicate that apratoxin A binds to the Sec61 lateral gate in a manner that differs from cotransin, a substrate-selective Sec61 inhibitor...
May 19, 2016: Cell Chemical Biology
https://www.readbyqxmd.com/read/27161930/protein-o-mannosylation-in-the-early-secretory-pathway
#8
REVIEW
Patrick Neubert, Sabine Strahl
Protein O-mannosylation and N-glycosylation are essential post-translational modifications, which initiate in the endoplasmic reticulum (ER). In yeast, the two glycosylation machineries act at the Sec61 translocon complex where they can even compete for certain substrate proteins. N-linked glycans play a crucial role in the ER quality control of glycoproteins. In recent years, it became clear that in addition to its important functions for cell surface proteins, O-mannosylation impacts the ER protein homeostasis...
August 2016: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/27155805/toward-a-structural-understanding-of-co-translational-protein-translocation
#9
REVIEW
Rebecca M Voorhees, Ramanujan S Hegde
The translocation of most eukaryotic secreted and integral membrane proteins occurs co-translationally at the endoplasmic reticulum (ER). These nascent polypeptides are recognized on the ribosome by the signal recognition particle (SRP), targeted to the ER, and translocated across or inserted into the membrane by the Sec61 translocation channel. Structural analysis of these co-translational processes has been challenging due to the size, complexity, and flexibility of the targeting and translocation machinery...
August 2016: Current Opinion in Cell Biology
https://www.readbyqxmd.com/read/26973090/unlocking-the-bacterial-secy-translocon
#10
Robin A Corey, William J Allen, Joanna Komar, Simonas Masiulis, Sam Menzies, Alice Robson, Ian Collinson
The Sec translocon performs protein secretion and membrane protein insertion at the plasma membrane of bacteria and archaea (SecYEG/β), and the endoplasmic reticular membrane of eukaryotes (Sec61). Despite numerous structures of the complex, the mechanism underlying translocation of pre-proteins, driven by the ATPase SecA in bacteria, remains unresolved. Here we present a series of biochemical and computational analyses exploring the consequences of signal sequence binding to SecYEG. The data demonstrate that a signal sequence-induced movement of transmembrane helix 7 unlocks the translocon and that this conformational change is communicated to the cytoplasmic faces of SecY and SecE, involved in SecA binding...
April 5, 2016: Structure
https://www.readbyqxmd.com/read/26950603/crystal-structure-of-a-substrate-engaged-secy-protein-translocation-channel
#11
Long Li, Eunyong Park, JingJing Ling, Jessica Ingram, Hidde Ploegh, Tom A Rapoport
Hydrophobic signal sequences target secretory polypeptides to a protein-conducting channel formed by a heterotrimeric membrane protein complex, the prokaryotic SecY or eukaryotic Sec61 complex. How signal sequences are recognized is poorly understood, particularly because they are diverse in sequence and length. Structures of the inactive channel show that the largest subunit, SecY or Sec61α, consists of two halves that form an hourglass-shaped pore with a constriction in the middle of the membrane and a lateral gate that faces lipid...
March 17, 2016: Nature
https://www.readbyqxmd.com/read/26923573/components-and-mechanisms-of-import-modification-folding-and-assembly-of-immunoglobulins-in-the-endoplasmic-reticulum
#12
Richard Zimmermann
In mammalian cells, the endoplasmic reticulum (ER) plays a central role in biogenesis of secretory- and plasma membrane proteins as well as in cellular calcium (Ca(2+)) homeostasis. The protein biogenesis function involves an aqueous polypeptide conducting channel in the ER membrane, which is formed by the heterotrimeric Sec61 complex; the store- and receptor-controlled Ca(2+)- release function requires a steep ER to cytosol gradient, with more than 500 μM free Ca(2+) in the ER and 50 nM Ca(2+) in the cytosol...
May 2016: Journal of Clinical Immunology
https://www.readbyqxmd.com/read/26869228/mechanistic-insights-into-the-inhibition-of-sec61-dependent-co-and-post-translational-translocation-by-mycolactone
#13
Michael McKenna, Rachel E Simmonds, Stephen High
The virulence factor mycolactone is responsible for the immunosuppression and tissue necrosis that characterise Buruli ulcer, a disease caused by infection with Mycobacterium ulcerans In this study, we confirm that Sec61, the protein-conducting channel that coordinates entry of secretory proteins into the endoplasmic reticulum, is a primary target of mycolactone, and characterise the nature of its inhibitory effect. We conclude that mycolactone constrains the ribosome-nascent-chain-Sec61 complex, consistent with its broad-ranging perturbation of the co-translational translocation of classical secretory proteins...
April 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/26823014/stability-and-flexibility-of-marginally-hydrophobic-segment-stalling-at-the-endoplasmic-reticulum-translocon
#14
Yuichiro Kida, Yudai Ishihara, Hidenobu Fujita, Yukiko Onishi, Masao Sakaguchi
Many membrane proteins are integrated into the endoplasmic reticulum membrane through the protein-conducting channel, the translocon. Transmembrane segments with insufficient hydrophobicity for membrane integration are frequently found in multispanning membrane proteins, and such marginally hydrophobic (mH) segments should be accommodated, at least transiently, at the membrane. Here we investigated how mH-segments stall at the membrane and their stability. Our findings show that mH-segments can be retained at the membrane without moving into the lipid phase and that such segments flank Sec61α, the core channel of the translocon, in the translational intermediate state...
March 15, 2016: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/26789921/targeting-viral-proteostasis-limits-influenza-virus-hiv-and-dengue-virus-infection
#15
Nicholas S Heaton, Natasha Moshkina, Romain Fenouil, Thomas J Gardner, Sebastian Aguirre, Priya S Shah, Nan Zhao, Lara Manganaro, Judd F Hultquist, Justine Noel, David Sachs, David H Sachs, Jennifer Hamilton, Paul E Leon, Amit Chawdury, Shashank Tripathi, Camilla Melegari, Laura Campisi, Rong Hai, Giorgi Metreveli, Andrea V Gamarnik, Adolfo García-Sastre, Benjamin Greenbaum, Viviana Simon, Ana Fernandez-Sesma, Nevan J Krogan, Lubbertus C F Mulder, Harm van Bakel, Domenico Tortorella, Jack Taunton, Peter Palese, Ivan Marazzi
Viruses are obligate parasites and thus require the machinery of the host cell to replicate. Inhibition of host factors co-opted during active infection is a strategy hosts use to suppress viral replication and a potential pan-antiviral therapy. To define the cellular proteins and processes required for a virus during infection is thus crucial to understanding the mechanisms of virally induced disease. In this report, we generated fully infectious tagged influenza viruses and used infection-based proteomics to identify pivotal arms of cellular signaling required for influenza virus growth and infectivity...
January 19, 2016: Immunity
https://www.readbyqxmd.com/read/26747607/determination-of-the-oligomeric-state-of-secyeg-protein-secretion-channel-complex-using-in-vivo-photo-and-disulfide-cross-linking
#16
Zeliang Zheng, Amy Blum, Tithi Banerjee, Qianyu Wang, Virginia Dantis, Donald Oliver
SecYEG protein of bacteria or Sec61αβγ of eukaryotes is a universally conserved heterotrimeric protein channel complex that accommodates the partitioning of membrane proteins into the lipid bilayer as well as the secretion of proteins to the trans side of the plasma or endoplasmic reticular membrane, respectively. SecYEG function is facilitated by cytosolic partners, mainly a nascent chain-ribosome complex or the SecA ATPase motor protein. Extensive efforts utilizing both biochemical and biophysical approaches have been made to determine whether SecYEG functions as a monomer or a dimer, but such approaches have often generated conflicting results...
March 11, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/26721998/structure-of-the-sec61-channel-opened-by-a-signal-sequence
#17
Rebecca M Voorhees, Ramanujan S Hegde
Secreted and integral membrane proteins compose up to one-third of the biological proteome. These proteins contain hydrophobic signals that direct their translocation across or insertion into the lipid bilayer by the Sec61 protein-conducting channel. The molecular basis of how hydrophobic signals within a nascent polypeptide trigger channel opening is not understood. Here, we used cryo-electron microscopy to determine the structure of an active Sec61 channel that has been opened by a signal sequence. The signal supplants helix 2 of Sec61α, which triggers a rotation that opens the central pore both axially across the membrane and laterally toward the lipid bilayer...
January 1, 2016: Science
https://www.readbyqxmd.com/read/26634806/mammalian-srp-receptor-switches-the-sec61-translocase-from-sec62-to-srp-dependent-translocation
#18
Bhalchandra Jadhav, Michael McKenna, Nicholas Johnson, Stephen High, Irmgard Sinning, Martin R Pool
Two distinct pathways deliver secretory proteins to the Sec61 protein translocase in the endoplasmic reticulum membrane. The canonical pathway requires the signal recognition particle (SRP) and its cognate receptor (SR), and targets ribosome-associated proteins to the Sec translocase. The SRP-independent pathway requires the Sec translocase-associated ER membrane protein Sec62 and can be uncoupled from translation. Here we show that SR switches translocons to SRP-dependent translocation by displacing Sec62...
December 4, 2015: Nature Communications
https://www.readbyqxmd.com/read/26572236/human-peroxin-pex3-is-co-translationally-integrated-into-the-er-and-exits-the-er-in%C3%A2-budding-vesicles
#19
Peter U Mayerhofer, Manuel Bañó-Polo, Ismael Mingarro, Arthur E Johnson
The long-standing paradigm that all peroxisomal proteins are imported post-translationally into pre-existing peroxisomes has been challenged by the detection of peroxisomal membrane proteins (PMPs) inside the endoplasmic reticulum (ER). In mammals, the mechanisms of ER entry and exit of PMPs are completely unknown. We show that the human PMP PEX3 inserts co-translationally into the mammalian ER via the Sec61 translocon. Photocrosslinking and fluorescence spectroscopy studies demonstrate that the N-terminal transmembrane segment (TMS) of ribosome-bound PEX3 is recognized by the signal recognition particle (SRP)...
February 2016: Traffic
https://www.readbyqxmd.com/read/26510791/sec66-dependent-regulation-of-yeast-spindle-pole-body-duplication-through-pom152
#20
Santharam S Katta, Jingjing Chen, Jennifer M Gardner, Jennifer M Friederichs, Sarah E Smith, Madelaine Gogol, Jay R Unruh, Brian D Slaughter, Sue L Jaspersen
In closed mitotic systems such as Saccharomyces cerevisiae, the nuclear envelope (NE) does not break down during mitosis, so microtubule-organizing centers such as the spindle-pole body (SPB) must be inserted into the NE to facilitate bipolar spindle formation and chromosome segregation. The mechanism of SPB insertion has been linked to NE insertion of nuclear pore complexes (NPCs) through a series of genetic and physical interactions between NPCs and SPB components. To identify new genes involved in SPB duplication and NE insertion, we carried out genome-wide screens for suppressors of deletion alleles of SPB components, including Mps3 and Mps2...
December 2015: Genetics
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