| Status: waiting for Mol* initialization | |
|
Structural highlights
Function
[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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
Misfolded endoplasmic reticulum proteins are retro-translocated through the membrane into the cytosol, where they are poly-ubiquitinated, extracted from the membrane, and degraded by the proteasome-a pathway termed endoplasmic reticulum-associated protein degradation (ERAD). Proteins with misfolded domains in the endoplasmic reticulum lumen or membrane are discarded through the ERAD-L and ERAD-M pathways, respectively. In Saccharomyces cerevisiae, both pathways require the ubiquitin ligase Hrd1, a multi-spanning membrane protein with a cytosolic RING finger domain. Hrd1 is the crucial membrane component for retro-translocation, but it is unclear whether it forms a protein-conducting channel. Here we present a cryo-electron microscopy structure of S. cerevisiae Hrd1 in complex with its endoplasmic reticulum luminal binding partner, Hrd3. Hrd1 forms a dimer within the membrane with one or two Hrd3 molecules associated at its luminal side. Each Hrd1 molecule has eight transmembrane segments, five of which form an aqueous cavity extending from the cytosol almost to the endoplasmic reticulum lumen, while a segment of the neighbouring Hrd1 molecule forms a lateral seal. The aqueous cavity and lateral gate are reminiscent of features of protein-conducting conduits that facilitate polypeptide movement in the opposite direction-from the cytosol into or across membranes. Our results suggest that Hrd1 forms a retro-translocation channel for the movement of misfolded polypeptides through the endoplasmic reticulum membrane.
Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3.,Schoebel S, Mi W, Stein A, Ovchinnikov S, Pavlovicz R, DiMaio F, Baker D, Chambers MG, Su H, Li D, Rapoport TA, Liao M Nature. 2017 Aug 17;548(7667):352-355. doi: 10.1038/nature23314. Epub 2017 Jul 6. PMID:28682307[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ 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:https://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:https://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:https://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
- ↑ Schoebel S, Mi W, Stein A, Ovchinnikov S, Pavlovicz R, DiMaio F, Baker D, Chambers MG, Su H, Li D, Rapoport TA, Liao M. Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex with Hrd3. Nature. 2017 Aug 17;548(7667):352-355. doi: 10.1038/nature23314. Epub 2017 Jul 6. PMID:28682307 doi:https://dx.doi.org/10.1038/nature23314
|
