ERAD substrates

Definition:

Glycosylated:

Non-glycosylated:

Physiological ERAD substrates:
 * HMG-CoA reductase (3-hydroxy-3-methylglutaryl coenzyme A)
 * HRD dependent substrate; absence of lectins (Yos9/OS-9/XTP3-B) does not affect its degradation
 * Hmg2p in yeast: rate-limiting enzyme in cholesterol synthesis; when cholesterol levels are high, Hmg2p undergoes lipid-induced structural change so that it resembles a misfolded protein --> targeted for degradation to Hrd1p (circumvents need for adaptor proteins such as Usa1p, Der1p or Yos9p)
 * mammalian HMG-CoA reductase: also regulated via degradation
 * Apolipoportein B (apoB): 
 * involved in delivery of cholesterol to tissues
 * co-translationally degraded if not adequately loaded with cargo (Brodsky & Fisher, 2008; Trends Endocrinol Metab)
 * Erg3p: component of sterol biosynthesis pathway in yeast; also endogenous ERAD substrate

 ERAD substrates 

 

 in yeast: 

   

 in mammals:  



 in plants: 











 o     Bernasconi , Riccardo, Carmela Galli, Verena Calanca, Toshihiro Nakajima, and Maurizio Molinari. 2010. “Stringent requirement for HRD1, SEL1L, and OS-9/XTP3-B for disposal of ERAD-LS substrates.” The Journal of cell biology 188 (2) (January): 223-35. doi:10.1083/jcb.200910042. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2812524&tool=pmcentrez&rendertype=abstract.

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">Cabral <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> Christoph M., Liu Yan, Moremen Kelley W., Sifers Richard N. 2002. Mol Biol Cell:13:2639-2650

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     ''<span style="font-size:9.0pt;font-family: "Calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-hansi-theme-font: minor-latin;mso-bidi-font-family:Arial;color:#31849B;mso-themecolor:accent5; mso-themeshade:191">Christianson <span style="font-size:9.0pt;font-family:"Calibri","sans-serif"; mso-ascii-theme-font:minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family: Arial;color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, John C, Thomas A Shaler, Ryan E Tyler, and Ron R Kopito. 2008. “OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.” Nature Cell biology 10 (March): 272-282. doi:10.1038/ncb1689. ''

<p style="text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;line-height:115%;font-family:"Courier New";mso-fareast-font-family: "Courier New";color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     <span style="font-size:9.0pt;line-height: 115%;mso-bidi-font-family:Arial;color:#31849B;mso-themecolor:accent5; mso-themeshade:191">Hirao <span style="font-size:9.0pt;line-height:115%;mso-bidi-font-family:Arial;color:#31849B; mso-themecolor:accent5;mso-themeshade:191"> K, Natsuka Y, Tamura T, <span style="font-size:9.0pt;line-height:115%;mso-bidi-font-family:Arial;color:#31849B; mso-themecolor:accent5;mso-themeshade:191">Wada I, Morito D, Natsuka S, et al. EDEM3, a soluble EDEM homolog, enhances glycoprotein ERAD and mannose trimming. J Biol Chem 2006;281:9650.

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">Hosokawa <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, N, I Wada, K Hasegawa, T Yorihuzi, L O Tremblay, a Herscovics, and K Nagata. 2001. “A novel ER alpha-mannosidase-like protein accelerates ER-associated degradation.” EMBO reports 2 (5) (May): 415-22. doi:10.1093/embo-reports/kve084. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1083879&tool=pmcentrez&rendertype=abstract.

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">Hosokawa <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, Nobuko, Linda O Tremblay, Zhipeng You, Annette Herscovics, Ikuo Wada, and Kazuhiro Nagata. 2003. “Enhancement of endoplasmic reticulum (ER) degradation of misfolded Null Hong Kong alpha1-antitrypsin by human ER mannosidase I.” The Journal of biological chemistry 278 (28) (July): 26287-94. doi:10.1074/jbc.M303395200. http://www.ncbi.nlm.nih.gov/pubmed/12736254.

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">Hosomi <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, Akira, Kaori Tanabe, Hiroto Hirayama, Ikjin Kim, Hai Rao, and Tadashi Suzuki. 2010. “Identification of an Htm1 (EDEM)-dependent, Mns1-independent ERAD pathway in Saccharomyces cerevisiae.” <span style="mso-bidi-font-style: italic">The Journal of biological chemistry 285 (32) (June): 24324 -24334. doi:10.1074/jbc.M109.095919. <span style="color:#31849B; mso-themecolor:accent5;mso-themeshade:191">http://www.ncbi.nlm.nih.gov/pubmed/20511219.

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     ''<span style="font-size:9.0pt;font-family: "Calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-hansi-theme-font: minor-latin;mso-bidi-font-family:Arial;color:#31849B;mso-themecolor:accent5; mso-themeshade:191">Mast <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, Steven W, Krista Diekman, Khanita Karaveg, Ann Davis, Richard N Sifers, and Kelley W Moremen. 2005. “Human EDEM2, a novel homolog of family 47 glycosidases, is involved in ER-associated degradation of glycoproteins.” Glycobiology 15 (4) (April): 421-36. doi:10.1093/glycob/cwi014. http://www.ncbi.nlm.nih.gov/pubmed/15537790. ''

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">Molinari <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, Maurizio, Verena Calanca, Carmela Galli, Paola Lucca, and Paolo Paganetti. 2003. “Role of EDEM in the release of misfolded glycoproteins from the calnexin cycle.” Science (New York, N.Y.) 299 (5611) (February): 1397-400. doi:10.1126/science.1079474. http://www.ncbi.nlm.nih.gov/pubmed/12610306.

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     ''<span style="font-size:9.0pt;font-family: "Calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-hansi-theme-font: minor-latin;mso-bidi-font-family:Arial;color:#31849B;mso-themecolor:accent5; mso-themeshade:191">Molinari <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, Maurizio, Carmela Galli, Verena Piccaluga, Michel Pieren, and Paolo Paganetti. 2002. “Sequential assistance of molecular chaperones and transient formation of covalent complexes during protein degradation from the ER.” The Journal of cell biology 158 (2) (July): 247-57. doi:10.1083/jcb.200204122. http://www.ncbi.nlm.nih.gov/pubmed/12119363. ''

<p style="margin-left:.5in;text-align:justify;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     ''<span style="font-size:9.0pt;font-family: "Calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-hansi-theme-font: minor-latin;mso-bidi-font-family:Arial;color:#31849B;mso-themecolor:accent5; mso-themeshade:191">Müller <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, Judith, Pietro Piffanelli, Alessandra Devoto, Marco Miklis, Candace Elliott, Bodo Ortmann, Paul Schulze-Lefert, and Ralph Panstruga. 2005. “Conserved ERAD-Like Quality Control of a Plant Polytopic Membrane Protein.” The Plant Cell 17 (January): 149-163. doi:10.1105/tpc.104.026625.1. ''

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     ''<span style="font-size:9.0pt;font-family: "Calibri","sans-serif";mso-ascii-theme-font:minor-latin;mso-hansi-theme-font: minor-latin;mso-bidi-font-family:Arial;color:#31849B;mso-themecolor:accent5; mso-themeshade:191">Olivari <span style="font-size:9.0pt;font-family:"Calibri","sans-serif";mso-ascii-theme-font: minor-latin;mso-hansi-theme-font:minor-latin;mso-bidi-font-family:Arial; color:#31849B;mso-themecolor:accent5;mso-themeshade:191">, Silvia, Carmela Galli, Heli Alanen, Lloyd Ruddock, and Maurizio Molinari. 2005. “A novel stress-induced EDEM variant regulating endoplasmic reticulum-associated glycoprotein degradation.” <span style="mso-bidi-font-style: italic">The Journal of biological chemistry 280 (4) (January): 2424-8. doi:10.1074/jbc.C400534200. http://www.ncbi.nlm.nih.gov/pubmed/15579471. ''

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-size:9.0pt;font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o     <span style="font-size:9.0pt;font-family:"Arial","sans-serif";color:#31849B; mso-themecolor:accent5;mso-themeshade:191"> 

<p style="margin-left:.5in;text-indent:-.25in;mso-list:l5 level1 lfo10"><span style="font-family:"Courier New";mso-fareast-font-family:"Courier New"; color:#31849B;mso-themecolor:accent5;mso-themeshade:191"> o    <span style="font-family:"Arial","sans-serif";color:#31849B;mso-themecolor:accent5; mso-themeshade:191">