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  • 1
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    A ribosome-associating factor chaperones tail-anchored membrane proteins (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-08-03
    Description: Hundreds of proteins are inserted post-translationally into the endoplasmic reticulum (ER) membrane by a single carboxy-terminal transmembrane domain (TMD). During targeting through the cytosol, the hydrophobic TMD of these tail-anchored (TA) proteins requires constant chaperoning to prevent aggregation or inappropriate interactions. A central component of this targeting system is TRC40, a conserved cytosolic factor that recognizes the TMD of TA proteins and delivers them to the ER for insertion. The mechanism that permits TRC40 to find and capture its TA protein cargos effectively in a highly crowded cytosol is unknown. Here we identify a conserved three-protein complex composed of Bat3, TRC35 and Ubl4A that facilitates TA protein capture by TRC40. This Bat3 complex is recruited to ribosomes synthesizing membrane proteins, interacts with the TMDs of newly released TA proteins, and transfers them to TRC40 for targeting. Depletion of the Bat3 complex allows non-TRC40 factors to compete for TA proteins, explaining their mislocalization in the analogous yeast deletion strains. Thus, the Bat3 complex acts as a TMD-selective chaperone that effectively channels TA proteins to the TRC40 insertion pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928861/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928861/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mariappan, Malaiyalam -- Li, Xingzhe -- Stefanovic, Sandra -- Sharma, Ajay -- Mateja, Agnieszka -- Keenan, Robert J -- Hegde, Ramanujan S -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- ZIA HD008862-02/Intramural NIH HHS/ -- England -- Nature. 2010 Aug 26;466(7310):1120-4. doi: 10.1038/nature09296. Epub 2010 Aug 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20676083" target="_blank"〉PubMed〈/a〉
    Keywords: Carrier Proteins/metabolism ; Endoplasmic Reticulum/metabolism ; Humans ; Membrane Proteins/*metabolism ; Molecular Chaperones/*metabolism ; Protein Transport ; Ribosomes/*metabolism ; Signal Recognition Particle/metabolism ; Ubiquitins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    The mechanism of membrane-associated steps in tail-anchored protein insertion (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-08-26
    Description: Tail-anchored (TA) membrane proteins destined for the endoplasmic reticulum are chaperoned by cytosolic targeting factors that deliver them to a membrane receptor for insertion. Although a basic framework for TA protein recognition is now emerging, the decisive targeting and membrane insertion steps are not understood. Here we reconstitute the TA protein insertion cycle with purified components, present crystal structures of key complexes between these components and perform mutational analyses based on the structures. We show that a committed targeting complex, formed by a TA protein bound to the chaperone ATPase Get3, is initially recruited to the membrane through an interaction with Get2. Once the targeting complex has been recruited, Get1 interacts with Get3 to drive TA protein release in an ATPase-dependent reaction. After releasing its TA protein cargo, the now-vacant Get3 recycles back to the cytosol concomitant with ATP binding. This work provides a detailed structural and mechanistic framework for the minimal TA protein insertion cycle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760497/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3760497/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mariappan, Malaiyalam -- Mateja, Agnieszka -- Dobosz, Malgorzata -- Bove, Elia -- Hegde, Ramanujan S -- Keenan, Robert J -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- R01 GM086487/GM/NIGMS NIH HHS/ -- R01GM086487/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Aug 24;477(7362):61-6. doi: 10.1038/nature10362.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21866104" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Endoplasmic Reticulum/metabolism ; Membrane Proteins/chemistry/*metabolism ; Models, Molecular ; Protein Transport ; Saccharomyces cerevisiae/metabolism/*physiology ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Protein targeting and degradation are coupled for elimination of mislocalized proteins (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-12
    Description: A substantial proportion of the genome encodes membrane proteins that are delivered to the endoplasmic reticulum by dedicated targeting pathways. Membrane proteins that fail targeting must be rapidly degraded to avoid aggregation and disruption of cytosolic protein homeostasis. The mechanisms of mislocalized protein (MLP) degradation are unknown. Here we reconstitute MLP degradation in vitro to identify factors involved in this pathway. We find that nascent membrane proteins tethered to ribosomes are not substrates for ubiquitination unless they are released into the cytosol. Their inappropriate release results in capture by the Bag6 complex, a recently identified ribosome-associating chaperone. Bag6-complex-mediated capture depends on the presence of unprocessed or non-inserted hydrophobic domains that distinguish MLPs from potential cytosolic proteins. A subset of these Bag6 complex 'clients' are transferred to TRC40 for insertion into the membrane, whereas the remainder are rapidly ubiquitinated. Depletion of the Bag6 complex selectively impairs the efficient ubiquitination of MLPs. Thus, by its presence on ribosomes that are synthesizing nascent membrane proteins, the Bag6 complex links targeting and ubiquitination pathways. We propose that such coupling allows the fast tracking of MLPs for degradation without futile engagement of the cytosolic folding machinery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150218/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hessa, Tara -- Sharma, Ajay -- Mariappan, Malaiyalam -- Eshleman, Heather D -- Gutierrez, Erik -- Hegde, Ramanujan S -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- ZIA HD008861-02/Intramural NIH HHS/ -- England -- Nature. 2011 Jul 10;475(7356):394-7. doi: 10.1038/nature10181.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21743475" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arsenite Transporting ATPases/metabolism ; Cattle ; Cell Membrane/metabolism ; Cytoplasm/metabolism ; Endoplasmic Reticulum/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Molecular Chaperones/metabolism ; Multiprotein Complexes/metabolism ; Neuropeptide Y/chemistry ; Prions/chemistry/*metabolism ; Prolactin/chemistry ; Proteasome Endopeptidase Complex/metabolism ; Protein Folding ; Protein Precursors/chemistry ; Protein Sorting Signals/physiology ; Protein Structure, Tertiary ; Protein Transport ; Ribosomes/metabolism ; Ubiquitin/metabolism ; *Ubiquitination
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Protein targeting. Structure of the Get3 targeting factor in complex with its membrane protein cargo (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-03-07
    Description: Tail-anchored (TA) proteins are a physiologically important class of membrane proteins targeted to the endoplasmic reticulum by the conserved guided-entry of TA proteins (GET) pathway. During transit, their hydrophobic transmembrane domains (TMDs) are chaperoned by the cytosolic targeting factor Get3, but the molecular nature of the functional Get3-TA protein targeting complex remains unknown. We reconstituted the physiologic assembly pathway for a functional targeting complex and showed that it comprises a TA protein bound to a Get3 homodimer. Crystal structures of Get3 bound to different TA proteins showed an alpha-helical TMD occupying a hydrophobic groove that spans the Get3 homodimer. Our data elucidate the mechanism of TA protein recognition and shielding by Get3 and suggest general principles of hydrophobic domain chaperoning by cellular targeting factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413028/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mateja, Agnieszka -- Paduch, Marcin -- Chang, Hsin-Yang -- Szydlowska, Anna -- Kossiakoff, Anthony A -- Hegde, Ramanujan S -- Keenan, Robert J -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM086487/GM/NIGMS NIH HHS/ -- U01 GM094588/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1152-5. doi: 10.1126/science.1261671.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. ; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. rhegde@mrc-lmb.cam.ac.uk bkeenan@uchicago.edu. ; Department of Biochemistry and Molecular Biology, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. rhegde@mrc-lmb.cam.ac.uk bkeenan@uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25745174" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/*chemistry/metabolism ; Crystallography, X-Ray ; Cytosol/enzymology ; Guanine Nucleotide Exchange Factors/*chemistry/metabolism ; Hydrophobic and Hydrophilic Interactions ; Membrane Proteins/*chemistry/metabolism ; Molecular Chaperones/chemistry/metabolism ; Multiprotein Complexes/chemistry/metabolism ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Transport ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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