| Structural highlights
6vjz is a 4 chain structure with sequence from Atcc 18824. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Gene: | DER1 (ATCC 18824), HRD1, DER3 (ATCC 18824), HRD3 (ATCC 18824), USA1 (ATCC 18824) |
| Activity: | RING-type E3 ubiquitin transferase, with EC number 2.3.2.27 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[USA1_YEAST] Scaffold protein of the endoplasmic reticulum-associated degradation (ERAD) (also known as endoplasmic reticulum quality control, ERQC) pathway involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins. Component of the HRD1 ubiquitin ligase complex, which is part of the ERAD-L and ERAD-M pathways responsible for the rapid degradation of soluble lumenal and membrane proteins with misfolded lumenal domains (ERAD-L), or ER-membrane proteins with misfolded transmembrane domains (ERAD-M). Has multiple functions in ERAD including recruitment of DER1 to the HRD1 ubiquitin ligase, and regulation of HRD1 activity. Involved in oligomerization of HRD1, which is required for ERAD-L, and in HRD1 autoubiquitination and degradation.[1] [2] [3] [4] [5] [DER1_YEAST] Component of the endoplasmic reticulum-associated degradation (ERAD) pathway. Specifically required for the ERAD-L pathway which mediates the degradation of proteins with misfolded lumenal domains within the endoplasmic reticulum.[6] [7] [8] [9] [HRD3_YEAST] Component of the endoplasmic reticulum quality control (ERQC) system involved in ubiquitin-dependent degradation of missfolded endoplasmic reticulum proteins. Component of the HRD1 ubiquitin ligase complex, which is part of the ERAD-L and ERAD-M pathways responsible for the rapid degradation of soluble lumenal and membrane proteins with misfolded lumenal domains (ERAD-L), or ER-membrane proteins with misfolded transmembrane domains (ERAD-M). ERAD-L substrates are ubiquitinated through HRD1 in conjunction with the E2 ubiquitin-conjugating enzymes UBC1 and UBC7-CUE1. Ubiquitinated substrates are then removed to the cytosol via the action of the UFD1-NPL4-CDC48/p97 (UNC) AAA ATPase complex and targeted to the proteasome. ERAD-M substrates are processed by the same HRD1-HRD3 core complex, but only a subset of the other components is required for ERAD-M. Stabilizes the HRD1 ubiquitin-protein ligase. Has also a function in recruiting misfolded protein substrates.[10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [HRD1_YEAST] E3 ubiquitin-protein ligase which accepts ubiquitin specifically from endoplasmic reticulum-associated UBC1 and UBC7 E2 ligases, and transfers it to substrates promoting their degradation. Mediates the degradation of endoplasmic reticulum proteins (ERQC), also called ER-associated degradation (ERAD). Component of the HRD1 ubiquitin ligase complex, which is part of the ERAD-L and ERAD-M pathways responsible for the rapid degradation of soluble lumenal and membrane proteins with misfolded lumenal domains (ERAD-L), or ER-membrane proteins with misfolded transmembrane domains (ERAD-M). ERAD-L substrates are ubiquitinated through HRD1 in conjunction with the E2 ubiquitin-conjugating enzymes UBC1 and UBC7-CUE1. Ubiquitinated substrates are then removed to the cytosol via the action of the UFD1-NPL4-CDC48/p97 (UNC) AAA ATPase complex and targeted to the proteasome. ERAD-M substrates are processed by the same HRD1-HRD3 core complex, but only a subset of the other components is required for ERAD-M.[20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32]
Publication Abstract from PubMed
Misfolded luminal endoplasmic reticulum (ER) proteins undergo ER-associated degradation (ERAD-L): They are retrotranslocated into the cytosol, polyubiquitinated, and degraded by the proteasome. ERAD-L is mediated by the Hrd1 complex (composed of Hrd1, Hrd3, Der1, Usa1, and Yos9), but the mechanism of retrotranslocation remains mysterious. Here, we report a structure of the active Hrd1 complex, as determined by cryo-electron microscopy analysis of two subcomplexes. Hrd3 and Yos9 jointly create a luminal binding site that recognizes glycosylated substrates. Hrd1 and the rhomboid-like Der1 protein form two "half-channels" with cytosolic and luminal cavities, respectively, and lateral gates facing one another in a thinned membrane region. These structures, along with crosslinking and molecular dynamics simulation results, suggest how a polypeptide loop of an ERAD-L substrate moves through the ER membrane.
Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex.,Wu X, Siggel M, Ovchinnikov S, Mi W, Svetlov V, Nudler E, Liao M, Hummer G, Rapoport TA Science. 2020 Apr 24;368(6489). pii: 368/6489/eaaz2449. doi:, 10.1126/science.aaz2449. PMID:32327568[33]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006 Jul 28;126(2):361-73. PMID:16873066 doi:10.1016/j.cell.2006.05.043
- ↑ Kim I, Li Y, Muniz P, Rao H. Usa1 protein facilitates substrate ubiquitylation through two separate domains. PLoS One. 2009 Oct 29;4(10):e7604. doi: 10.1371/journal.pone.0007604. PMID:19898607 doi:http://dx.doi.org/10.1371/journal.pone.0007604
- ↑ Carroll SM, Hampton RY. Usa1p is required for optimal function and regulation of the Hrd1p endoplasmic reticulum-associated degradation ubiquitin ligase. J Biol Chem. 2010 Feb 19;285(8):5146-56. doi: 10.1074/jbc.M109.067876. Epub 2009 , Nov 24. PMID:19940128 doi:http://dx.doi.org/10.1074/jbc.M109.067876
- ↑ Horn SC, Hanna J, Hirsch C, Volkwein C, Schutz A, Heinemann U, Sommer T, Jarosch E. Usa1 functions as a scaffold of the HRD-ubiquitin ligase. Mol Cell. 2009 Dec 11;36(5):782-93. doi: 10.1016/j.molcel.2009.10.015. PMID:20005842 doi:http://dx.doi.org/10.1016/j.molcel.2009.10.015
- ↑ Carvalho P, Stanley AM, Rapoport TA. Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell. 2010 Nov 12;143(4):579-91. doi: 10.1016/j.cell.2010.10.028. PMID:21074049 doi:http://dx.doi.org/10.1016/j.cell.2010.10.028
- ↑ Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006 Jul 28;126(2):361-73. PMID:16873066 doi:10.1016/j.cell.2006.05.043
- ↑ Horn SC, Hanna J, Hirsch C, Volkwein C, Schutz A, Heinemann U, Sommer T, Jarosch E. Usa1 functions as a scaffold of the HRD-ubiquitin ligase. Mol Cell. 2009 Dec 11;36(5):782-93. doi: 10.1016/j.molcel.2009.10.015. PMID:20005842 doi:http://dx.doi.org/10.1016/j.molcel.2009.10.015
- ↑ Zattas D, Adle DJ, Rubenstein EM, Hochstrasser M. N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1 ubiquitin-ligase activity toward luminal ER substrates. Mol Biol Cell. 2013 Apr;24(7):890-900. doi: 10.1091/mbc.E12-11-0838. Epub 2013, Jan 30. PMID:23363603 doi:http://dx.doi.org/10.1091/mbc.E12-11-0838
- ↑ Knop M, Finger A, Braun T, Hellmuth K, Wolf DH. Der1, a novel protein specifically required for endoplasmic reticulum degradation in yeast. EMBO J. 1996 Feb 15;15(4):753-63. PMID:8631297
- ↑ Bordallo J, Wolf DH. A RING-H2 finger motif is essential for the function of Der3/Hrd1 in endoplasmic reticulum associated protein degradation in the yeast Saccharomyces cerevisiae. FEBS Lett. 1999 Apr 9;448(2-3):244-8. PMID:10218484
- ↑ Plemper RK, Bordallo J, Deak PM, Taxis C, Hitt R, Wolf DH. Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation. J Cell Sci. 1999 Nov;112 ( Pt 22):4123-34. PMID:10547371
- ↑ Wilhovsky S, Gardner R, Hampton R. HRD gene dependence of endoplasmic reticulum-associated degradation. Mol Biol Cell. 2000 May;11(5):1697-708. PMID:10793145
- ↑ Gardner RG, Swarbrick GM, Bays NW, Cronin SR, Wilhovsky S, Seelig L, Kim C, Hampton RY. Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J Cell Biol. 2000 Oct 2;151(1):69-82. PMID:11018054
- ↑ Gardner RG, Shearer AG, Hampton RY. In vivo action of the HRD ubiquitin ligase complex: mechanisms of endoplasmic reticulum quality control and sterol regulation. Mol Cell Biol. 2001 Jul;21(13):4276-91. PMID:11390656 doi:10.1128/MCB.21.13.4276-4291.2001
- ↑ Gauss R, Sommer T, Jarosch E. The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. EMBO J. 2006 May 3;25(9):1827-35. Epub 2006 Apr 13. PMID:16619026 doi:http://dx.doi.org/10.1038/sj.emboj.7601088
- ↑ Gauss R, Jarosch E, Sommer T, Hirsch C. A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum quality control into the degradation machinery. Nat Cell Biol. 2006 Aug;8(8):849-54. Epub 2006 Jul 16. PMID:16845381 doi:http://dx.doi.org/10.1038/ncb1445
- ↑ Denic V, Quan EM, Weissman JS. A luminal surveillance complex that selects misfolded glycoproteins for ER-associated degradation. Cell. 2006 Jul 28;126(2):349-59. PMID:16873065 doi:http://dx.doi.org/10.1016/j.cell.2006.05.045
- ↑ Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006 Jul 28;126(2):361-73. PMID:16873066 doi:10.1016/j.cell.2006.05.043
- ↑ Hampton RY, Gardner RG, Rine J. Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol Biol Cell. 1996 Dec;7(12):2029-44. PMID:8970163
- ↑ Bordallo J, Wolf DH. A RING-H2 finger motif is essential for the function of Der3/Hrd1 in endoplasmic reticulum associated protein degradation in the yeast Saccharomyces cerevisiae. FEBS Lett. 1999 Apr 9;448(2-3):244-8. PMID:10218484
- ↑ Plemper RK, Bordallo J, Deak PM, Taxis C, Hitt R, Wolf DH. Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro-translocation complex mediating protein transport for ER degradation. J Cell Sci. 1999 Nov;112 ( Pt 22):4123-34. PMID:10547371
- ↑ Wilhovsky S, Gardner R, Hampton R. HRD gene dependence of endoplasmic reticulum-associated degradation. Mol Biol Cell. 2000 May;11(5):1697-708. PMID:10793145
- ↑ Gardner RG, Swarbrick GM, Bays NW, Cronin SR, Wilhovsky S, Seelig L, Kim C, Hampton RY. Endoplasmic reticulum degradation requires lumen to cytosol signaling. Transmembrane control of Hrd1p by Hrd3p. J Cell Biol. 2000 Oct 2;151(1):69-82. PMID:11018054
- ↑ Deak PM, Wolf DH. Membrane topology and function of Der3/Hrd1p as a ubiquitin-protein ligase (E3) involved in endoplasmic reticulum degradation. J Biol Chem. 2001 Apr 6;276(14):10663-9. Epub 2001 Jan 3. PMID:11139575 doi:http://dx.doi.org/10.1074/jbc.M008608200
- ↑ Bays NW, Gardner RG, Seelig LP, Joazeiro CA, Hampton RY. Hrd1p/Der3p is a membrane-anchored ubiquitin ligase required for ER-associated degradation. Nat Cell Biol. 2001 Jan;3(1):24-9. PMID:11146622 doi:10.1038/35050524
- ↑ Gardner RG, Shearer AG, Hampton RY. In vivo action of the HRD ubiquitin ligase complex: mechanisms of endoplasmic reticulum quality control and sterol regulation. Mol Cell Biol. 2001 Jul;21(13):4276-91. PMID:11390656 doi:10.1128/MCB.21.13.4276-4291.2001
- ↑ Gauss R, Sommer T, Jarosch E. The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate selection and Cdc48p recruitment. EMBO J. 2006 May 3;25(9):1827-35. Epub 2006 Apr 13. PMID:16619026 doi:http://dx.doi.org/10.1038/sj.emboj.7601088
- ↑ Carvalho P, Goder V, Rapoport TA. Distinct ubiquitin-ligase complexes define convergent pathways for the degradation of ER proteins. Cell. 2006 Jul 28;126(2):361-73. PMID:16873066 doi:10.1016/j.cell.2006.05.043
- ↑ Horn SC, Hanna J, Hirsch C, Volkwein C, Schutz A, Heinemann U, Sommer T, Jarosch E. Usa1 functions as a scaffold of the HRD-ubiquitin ligase. Mol Cell. 2009 Dec 11;36(5):782-93. doi: 10.1016/j.molcel.2009.10.015. PMID:20005842 doi:http://dx.doi.org/10.1016/j.molcel.2009.10.015
- ↑ Carvalho P, Stanley AM, Rapoport TA. Retrotranslocation of a misfolded luminal ER protein by the ubiquitin-ligase Hrd1p. Cell. 2010 Nov 12;143(4):579-91. doi: 10.1016/j.cell.2010.10.028. PMID:21074049 doi:http://dx.doi.org/10.1016/j.cell.2010.10.028
- ↑ Hampton RY, Gardner RG, Rine J. Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3-methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane protein. Mol Biol Cell. 1996 Dec;7(12):2029-44. PMID:8970163
- ↑ Bordallo J, Plemper RK, Finger A, Wolf DH. Der3p/Hrd1p is required for endoplasmic reticulum-associated degradation of misfolded lumenal and integral membrane proteins. Mol Biol Cell. 1998 Jan;9(1):209-22. PMID:9437001
- ↑ Wu X, Siggel M, Ovchinnikov S, Mi W, Svetlov V, Nudler E, Liao M, Hummer G, Rapoport TA. Structural basis of ER-associated protein degradation mediated by the Hrd1 ubiquitin ligase complex. Science. 2020 Apr 24;368(6489). pii: 368/6489/eaaz2449. doi:, 10.1126/science.aaz2449. PMID:32327568 doi:http://dx.doi.org/10.1126/science.aaz2449
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