| Structural highlights
Function
[OS9_YEAST] Lectin involved in the quality control of the secretory pathway. As a member of the endoplasmic reticulum-associated degradation lumenal (ERAD-L) surveillance system, targets misfolded endoplasmic reticulum lumenal glycoproteins for degradation. The recognition of targets is N-glycan specific.[1] [2] [3] [4] [5]
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[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Friedmann E, Salzberg Y, Weinberger A, Shaltiel S, Gerst JE. YOS9, the putative yeast homolog of a gene amplified in osteosarcomas, is involved in the endoplasmic reticulum (ER)-Golgi transport of GPI-anchored proteins. J Biol Chem. 2002 Sep 20;277(38):35274-81. Epub 2002 Jun 20. PMID:12077121 doi:http://dx.doi.org/10.1074/jbc.M201044200
- ↑ Buschhorn BA, Kostova Z, Medicherla B, Wolf DH. A genome-wide screen identifies Yos9p as essential for ER-associated degradation of glycoproteins. FEBS Lett. 2004 Nov 19;577(3):422-6. PMID:15556621 doi:http://dx.doi.org/S0014579304012773
- ↑ Bhamidipati A, Denic V, Quan EM, Weissman JS. Exploration of the topological requirements of ERAD identifies Yos9p as a lectin sensor of misfolded glycoproteins in the ER lumen. Mol Cell. 2005 Sep 16;19(6):741-51. PMID:16168370 doi:http://dx.doi.org/S1097-2765(05)01524-8
- ↑ Kim W, Spear ED, Ng DT. Yos9p detects and targets misfolded glycoproteins for ER-associated degradation. Mol Cell. 2005 Sep 16;19(6):753-64. PMID:16168371 doi:http://dx.doi.org/S1097-2765(05)01528-5
- ↑ Szathmary R, Bielmann R, Nita-Lazar M, Burda P, Jakob CA. Yos9 protein is essential for degradation of misfolded glycoproteins and may function as lectin in ERAD. Mol Cell. 2005 Sep 16;19(6):765-75. PMID:16168372 doi:http://dx.doi.org/S1097-2765(05)01557-1
- ↑ 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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