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</v:shapetype><v:shape id="Imagen_x0020_3" o:spid="_x0000_s1027" type="#_x0000_t75" alt="Descripción: QOLogo02b" style='position:absolute;margin-left:0;margin-top:-3.55pt;width:66.5pt;height:49.25pt;z-index:251657216;visibility:visible;mso-wrap-style:square;mso-width-percent:0;mso-height-percent:0;mso-wrap-distance-left:9pt;mso-wrap-distance-top:0;mso-wrap-distance-right:9pt;mso-wrap-distance-bottom:0;mso-position-horizontal:absolute;mso-position-horizontal-relative:text;mso-position-vertical:absolute;mso-position-vertical-relative:text;mso-width-percent:0;mso-height-percent:0;mso-width-relative:page;mso-height-relative:page'>
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</v:shape><![endif]--><![if !vml]><img width=89 height=66 src="cid:image005.png@01CD081B.385B0200" align=left hspace=12 alt="Descripción: QOLogo02b" v:shapes="Imagen_x0020_3"><![endif]><b><span style='font-size:14.0pt;font-family:"Times New Roman","serif"'>SEMINARIO DE QUIMICA ORGANICA 2012<o:p></o:p></span></b></p><p class=MsoNormal><b><span style='font-size:16.0pt;font-family:"Times New Roman","serif";color:#00B050'>Miércoles 28 de marzo, 11.00 hs<o:p></o:p></span></b></p><p class=MsoNormal><b><span style='font-size:12.0pt;font-family:"Times New Roman","serif"'>Aula de Seminario, Departamento de Química Orgánica, FCEyN<o:p></o:p></span></b></p><p class=MsoNormal style='text-align:justify'><b><span style='font-size:12.0pt;font-family:"Times New Roman","serif"'><o:p> </o:p></span></b></p><p class=MsoNormal align=center style='text-align:center'><b><span lang=EN-US style='font-size:16.0pt;font-family:"Times New Roman","serif";color:#002060'>Dr. Gerardo Lederkremer<o:p></o:p></span></b></p><p class=MsoNormal align=center style='text-align:center'><b><span lang=EN-US style='font-family:"Times New Roman","serif";color:#002060'><o:p> </o:p></span></b></p><p class=MsoNormal align=center style='text-align:center'><span lang=EN-US style='font-family:"Arial","sans-serif"'>Department of Cell Research and Immunology, George Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.</span><span lang=EN-US style='font-size:12.0pt;font-family:"Times New Roman","serif"'><o:p></o:p></span></p><p class=MsoNormal align=center style='text-align:center'><b><span lang=EN-US style='font-size:16.0pt;font-family:"Times New Roman","serif";color:#C00000'>Glycan dependent and independent protein quality control in the endoplasmic reticulum<o:p></o:p></span></b></p><p class=MsoNormal style='text-align:justify'><span lang=EN-US style='font-size:12.0pt;font-family:"Times New Roman","serif"'><o:p> </o:p></span></p><p class=MsoNormal style='text-align:justify;text-indent:35.4pt;text-autospace:none'><span lang=EN-US style='font-size:10.0pt'>The endoplasmic reticulum (ER) is the staging ground for secretory protein synthesis with distinct sites for entry, quality control, and exit. In the ER, most secretory proteins are N-glycosylated. The folding state of glycoproteins is revealed by specific modifications of their N-glycans. In mammalian cells the ER chaperones calnexin and calreticulin initially bind to the sugar chains if they possess only one terminal glucose residue that remains from the original precursor or after its readdition by the folding sensor UDP-Glc: glycoprotein glucosyltransferase. This enzyme transfers a glucose residue and allows re-association of calnexin if the folding of the glycoprotein is not complete. If proper folding cannot be achieved in a certain time frame, the glycoprotein molecules are targeted to ER-associated degradation (ERAD) by retrotranslocation to the cytosol and degradation by the ubiquitin- proteasome pathway. The decision to send a glycoprotein molecule to ERAD involves differential processing of its sugar chains. We determined that three or four mannose residues are excised from misfolded molecules and only one or two from folded molecules that exit to the Golgi. The trimming of </span><span style='font-size:10.0pt'></span><span lang=EN-US style='font-size:10.0pt'>1,2-mannose residues from the precursor N-linked oligosaccharides is an essential step in the delivery of misfolded glycoproteins to ERAD, and we and others have recently deciphered the role of this trimming. The removal of mannose residues abrogates the reglucosylation and calnexin binding cycles and enables delivery of a misfolded glycoprotein from the chaperone and mannosidase EDEM1 to late ERAD steps through association with the luminal ER lectins OS9 and XTP3-B. These processes take place in a subcellular compartment that we have termed the ER-derived quality control compartment (ERQC).</span><span lang=EN-US style='font-size:10.0pt'><o:p></o:p></span></p><p class=MsoNormal style='text-align:justify;text-indent:35.4pt;text-autospace:none'><span lang=EN-US style='font-size:10.0pt'><o:p> </o:p></span></p><p class=MsoNormal style='text-align:justify;text-indent:35.4pt;text-autospace:none'><span lang=EN-US style='font-size:10.0pt'>Accumulation of misfolded proteins causes ER stress. Surprisingly, we have found that under ER stress conditions, when EDEM1 is upregulated by the unfolded protein response, it delivers glycoproteins to OS9 and XTP3B and accelerates ERAD in a glycan-independent manner. This would help to rapidly alleviate the protein load under stress. We recently determined that also misfolded nonglycosylated proteins utilize EDEM1 and most of the components of “glycan-dependent” quality control. Our results suggest a shared ERAD pathway for glycoproteins and nonglycosylated proteins, through machinery components with lectin activity but also capable of protein-protein interactions, except for lectins on the cytosolic side of the ER membrane that target only glycoproteins.<o:p></o:p></span></p><p class=MsoNormal style='text-align:justify;text-indent:35.4pt;text-autospace:none'><span lang=EN-US style='font-size:10.0pt'><o:p> </o:p></span></p><p class=MsoNormal style='text-align:justify;text-indent:35.4pt;text-autospace:none'><span lang=EN-US style='font-size:10.0pt'><o:p> </o:p></span></p><p class=MsoNormal><!--[if gte vml 1]><v:shape id="_x0000_s1026" type="#_x0000_t75" alt="References: Lederkremer, G.Z. Glycoprotein folding, quality control and ER-associated degradation. Curr Opin Struct Biol. 19, 515-23 (2009). Groisman, B., Shenkman, M., Ron, E. and Lederkremer, G.Z. Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late ER-associated degradation steps. J. Biol. Chem. 286, 1292-300 (2011). Ron, E., Shenkman, M., Groisman, B., Izenshtein, Y., Leitman, J. and Lederkremer, G.Z. Bypass of glycan-dependent glycoprotein delivery to ERAD by upregulated EDEM1. Mol. Biol. Cell. 22, 3945-54 (2011). Benyair, R., Ron, E. and Lederkremer, G.Z. Protein quality control, retention and degradation at the endoplasmic reticulum. Int. Rev. Cell. Mol. Biol. 292, 197-280 (2011). " style='position:absolute;margin-left:264.8pt;margin-top:13.95pt;width:218.25pt;height:208.7pt;z-index:251658240;visibility:visible;mso-width-percent:0;mso-height-percent:0;mso-wrap-distance-left:9pt;mso-wrap-distance-top:0;mso-wrap-distance-right:9pt;mso-wrap-distance-bottom:0;mso-position-horizontal:absolute;mso-position-horizontal-relative:text;mso-position-vertical:absolute;mso-position-vertical-relative:text;mso-width-percent:0;mso-height-percent:0;mso-width-relative:margin;mso-height-relative:margin'>
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</v:shape><![endif]--><![if !vml]><span style='mso-ignore:vglayout;position:absolute;z-index:251658240;margin-left:353px;margin-top:19px;width:291px;height:278px'><img width=291 height=278 src="cid:image007.png@01CD081B.385B0200" alt="References: Lederkremer, G.Z. Glycoprotein folding, quality control and ER-associated degradation. Curr Opin Struct Biol. 19, 515-23 (2009). Groisman, B., Shenkman, M., Ron, E. and Lederkremer, G.Z. Mannose trimming is required for delivery of a glycoprotein from EDEM1 to XTP3-B and to late ER-associated degradation steps. J. Biol. Chem. 286, 1292-300 (2011). Ron, E., Shenkman, M., Groisman, B., Izenshtein, Y., Leitman, J. and Lederkremer, G.Z. Bypass of glycan-dependent glycoprotein delivery to ERAD by upregulated EDEM1. Mol. Biol. Cell. 22, 3945-54 (2011). Benyair, R., Ron, E. and Lederkremer, G.Z. Protein quality control, retention and degradation at the endoplasmic reticulum. Int. Rev. Cell. Mol. Biol. 292, 197-280 (2011). " v:shapes="_x0000_s1026"></span><![endif]><b><span style='font-size:12.0pt;mso-fareast-language:ES-AR'><img width=308 height=271 id="Imagen_x0020_1" src="cid:image008.jpg@01CD081B.385B0200"></span></b><span style='font-size:10.0pt;font-family:"Times New Roman","serif"'><o:p></o:p></span></p><p class=MsoNormal><o:p> </o:p></p><p class=MsoNormal><o:p> </o:p></p></div></body></html>