ID HRD3_YEAST Reviewed; 833 AA. AC Q05787; D6VYK8; DT 27-JUN-2006, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1996, sequence version 1. DT 27-MAR-2024, entry version 169. DE RecName: Full=ERAD-associated E3 ubiquitin-protein ligase component HRD3; DE AltName: Full=HMG-CoA reductase degradation protein 3; DE Flags: Precursor; GN Name=HRD3; OrderedLocusNames=YLR207W; OS Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast). OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes; OC Saccharomycetales; Saccharomycetaceae; Saccharomyces. OX NCBI_TaxID=559292; RN [1] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RC STRAIN=ATCC 204508 / S288c; RX PubMed=9169871; RA Johnston M., Hillier L.W., Riles L., Albermann K., Andre B., Ansorge W., RA Benes V., Brueckner M., Delius H., Dubois E., Duesterhoeft A., RA Entian K.-D., Floeth M., Goffeau A., Hebling U., Heumann K., RA Heuss-Neitzel D., Hilbert H., Hilger F., Kleine K., Koetter P., Louis E.J., RA Messenguy F., Mewes H.-W., Miosga T., Moestl D., Mueller-Auer S., RA Nentwich U., Obermaier B., Piravandi E., Pohl T.M., Portetelle D., RA Purnelle B., Rechmann S., Rieger M., Rinke M., Rose M., Scharfe M., RA Scherens B., Scholler P., Schwager C., Schwarz S., Underwood A.P., RA Urrestarazu L.A., Vandenbol M., Verhasselt P., Vierendeels F., Voet M., RA Volckaert G., Voss H., Wambutt R., Wedler E., Wedler H., Zimmermann F.K., RA Zollner A., Hani J., Hoheisel J.D.; RT "The nucleotide sequence of Saccharomyces cerevisiae chromosome XII."; RL Nature 387:87-90(1997). RN [2] RP GENOME REANNOTATION. RC STRAIN=ATCC 204508 / S288c; RX PubMed=24374639; DOI=10.1534/g3.113.008995; RA Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R., RA Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S., RA Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.; RT "The reference genome sequence of Saccharomyces cerevisiae: Then and now."; RL G3 (Bethesda) 4:389-398(2014). RN [3] RP FUNCTION. RX PubMed=8970163; DOI=10.1091/mbc.7.12.2029; RA Hampton R.Y., Gardner R.G., Rine J.; RT "Role of 26S proteasome and HRD genes in the degradation of 3-hydroxy-3- RT methylglutaryl-CoA reductase, an integral endoplasmic reticulum membrane RT protein."; RL Mol. Biol. Cell 7:2029-2044(1996). RN [4] RP FUNCTION. RX PubMed=10218484; DOI=10.1016/s0014-5793(99)00362-2; RA Bordallo J., Wolf D.H.; RT "A RING-H2 finger motif is essential for the function of Der3/Hrd1 in RT endoplasmic reticulum associated protein degradation in the yeast RT Saccharomyces cerevisiae."; RL FEBS Lett. 448:244-248(1999). RN [5] RP FUNCTION. RX PubMed=10547371; DOI=10.1242/jcs.112.22.4123; RA Plemper R.K., Bordallo J., Deak P.M., Taxis C., Hitt R., Wolf D.H.; RT "Genetic interactions of Hrd3p and Der3p/Hrd1p with Sec61p suggest a retro- RT translocation complex mediating protein transport for ER degradation."; RL J. Cell Sci. 112:4123-4134(1999). RN [6] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH HRD1. RX PubMed=11018054; DOI=10.1083/jcb.151.1.69; RA Gardner R.G., Swarbrick G.M., Bays N.W., Cronin S.R., Wilhovsky S., RA Seelig L.P., Kim C., Hampton R.Y.; RT "Endoplasmic reticulum degradation requires lumen to cytosol signaling. RT Transmembrane control of Hrd1p by Hrd3p."; RL J. Cell Biol. 151:69-82(2000). RN [7] RP FUNCTION. RX PubMed=10793145; DOI=10.1091/mbc.11.5.1697; RA Wilhovsky S., Gardner R.G., Hampton R.Y.; RT "HRD gene dependence of endoplasmic reticulum-associated degradation."; RL Mol. Biol. Cell 11:1697-1708(2000). RN [8] RP FUNCTION, AND INTERACTION WITH HMG1 AND HMG2. RX PubMed=11390656; DOI=10.1128/mcb.21.13.4276-4291.2001; RA Gardner R.G., Shearer A.G., Hampton R.Y.; RT "In vivo action of the HRD ubiquitin ligase complex: mechanisms of RT endoplasmic reticulum quality control and sterol regulation."; RL Mol. Cell. Biol. 21:4276-4291(2001). RN [9] RP FUNCTION, IDENTIFICATION IN THE HRD1 COMPLEX, AND INTERACTION WITH KAR2. RX PubMed=16873065; DOI=10.1016/j.cell.2006.05.045; RA Denic V., Quan E.M., Weissman J.S.; RT "A luminal surveillance complex that selects misfolded glycoproteins for RT ER-associated degradation."; RL Cell 126:349-359(2006). RN [10] RP FUNCTION, AND IDENTIFICATION IN THE HRD1 COMPLEX. RX PubMed=16873066; DOI=10.1016/j.cell.2006.05.043; RA Carvalho P., Goder V., Rapoport T.A.; RT "Distinct ubiquitin-ligase complexes define convergent pathways for the RT degradation of ER proteins."; RL Cell 126:361-373(2006). RN [11] RP FUNCTION, AND INTERACTION WITH CDC48 AND DER1. RX PubMed=16619026; DOI=10.1038/sj.emboj.7601088; RA Gauss R., Sommer T., Jarosch E.; RT "The Hrd1p ligase complex forms a linchpin between ER-lumenal substrate RT selection and Cdc48p recruitment."; RL EMBO J. 25:1827-1835(2006). RN [12] RP FUNCTION, AND INTERACTION WITH HRD1 AND YOS9. RX PubMed=16845381; DOI=10.1038/ncb1445; RA Gauss R., Jarosch E., Sommer T., Hirsch C.; RT "A complex of Yos9p and the HRD ligase integrates endoplasmic reticulum RT quality control into the degradation machinery."; RL Nat. Cell Biol. 8:849-854(2006). RN [13] RP INTERACTION WITH YOS9. RX PubMed=22262864; DOI=10.1074/jbc.m111.317644; RA Hanna J., Schuetz A., Zimmermann F., Behlke J., Sommer T., Heinemann U.; RT "Structural and biochemical basis of Yos9 protein dimerization and possible RT contribution to self-association of 3-hydroxy-3-methylglutaryl-coenzyme A RT reductase degradation ubiquitin-ligase complex."; RL J. Biol. Chem. 287:8633-8640(2012). RN [14] {ECO:0007744|PDB:5V7V} RP STRUCTURE BY ELECTRON MICROSCOPY (3.90 ANGSTROMS) OF 1-767 IN COMPLEX WITH RP HRD1. RX PubMed=28682307; DOI=10.1038/nature23314; RA Schoebel S., Mi W., Stein A., Ovchinnikov S., Pavlovicz R., DiMaio F., RA Baker D., Chambers M.G., Su H., Li D., Rapoport T.A., Liao M.; RT "Cryo-EM structure of the protein-conducting ERAD channel Hrd1 in complex RT with Hrd3."; RL Nature 548:352-355(2017). RN [15] {ECO:0007744|PDB:6VJY, ECO:0007744|PDB:6VJZ, ECO:0007744|PDB:6VK0, ECO:0007744|PDB:6VK1, ECO:0007744|PDB:6VK3} RP STRUCTURE BY ELECTRON MICROSCOPY (4.10 ANGSTROMS) OF 1-767 IN COMPLEX WITH RP DER1; HRD1 AND USA1, STRUCTURE BY ELECTRON MICROSCOPY (3.70 ANGSTROMS) OF RP 1-767 IN COMPLEX WITH YOS9, AND FUNCTION. RX PubMed=32327568; DOI=10.1126/science.aaz2449; RA Wu X., Siggel M., Ovchinnikov S., Mi W., Svetlov V., Nudler E., Liao M., RA Hummer G., Rapoport T.A.; RT "Structural basis of ER-associated protein degradation mediated by the Hrd1 RT ubiquitin ligase complex."; RL Science 368:0-0(2020). CC -!- FUNCTION: Component of the endoplasmic reticulum quality control (ERQC) CC system involved in ubiquitin-dependent degradation of misfolded CC endoplasmic reticulum proteins. Component of the HRD1 ubiquitin ligase CC complex, which is part of the ERAD-L and ERAD-M pathways responsible CC for the rapid degradation of soluble lumenal and membrane proteins with CC misfolded lumenal domains (ERAD-L), or ER-membrane proteins with CC misfolded transmembrane domains (ERAD-M). ERAD-L substrates are CC ubiquitinated through HRD1 in conjunction with the E2 ubiquitin- CC conjugating enzymes UBC1 and UBC7-CUE1. Ubiquitinated substrates are CC then removed to the cytosol via the action of the CDC48-NPL4-UFD1 CC ATPase complex and targeted to the proteasome. ERAD-M substrates are CC processed by the same HRD1-HRD3 core complex, but only a subset of the CC other components is required for ERAD-M. Stabilizes the HRD1 ubiquitin- CC protein ligase. Also functions in recruiting misfolded protein CC substrates in conjunction with YOS9. {ECO:0000269|PubMed:10218484, CC ECO:0000269|PubMed:10547371, ECO:0000269|PubMed:10793145, CC ECO:0000269|PubMed:11018054, ECO:0000269|PubMed:11390656, CC ECO:0000269|PubMed:16619026, ECO:0000269|PubMed:16845381, CC ECO:0000269|PubMed:16873065, ECO:0000269|PubMed:16873066, CC ECO:0000269|PubMed:32327568, ECO:0000269|PubMed:8970163}. CC -!- SUBUNIT: Component of the HRD1 ubiquitin ligase complex which contains CC the E3 ligase HRD1, its cofactors HRD3, USA1 and DER1, substrate CC recruiting factor YOS9 and CDC48-binding protein UBX2 (PubMed:16873065, CC PubMed:16873066, PubMed:16845381). Within the complex, interacts CC directly with HRD1 and YOS9 (via N-terminus) (PubMed:11018054, CC PubMed:22262864, PubMed:28682307). In ERAD-L, HRD3 and YOS9 jointly CC bind misfolded glycoproteins in the endoplasmic reticulum (ER) lumen CC (PubMed:32327568). Movement of ERAD-L substrates through the ER CC membrane is facilitated by HRD1 and DER1 which have lateral gates CC facing each other and which distort the membrane region between the CC lateral gates, making it much thinner than a normal phospholipid CC bilayer (PubMed:32327568). Substrates insert into the membrane as a CC hairpin loop with one strand interacting with DER1 and the other with CC HRD1 (PubMed:32327568). The HRD1 complex interacts with the CC heterotrimeric CDC48-NPL4-UFD1 ATPase complex which is recruited by CC UBX2 via its interaction with CDC48 and which moves ubiquitinated CC substrates to the cytosol for targeting to the proteasome CC (PubMed:16873066, PubMed:16619026). The HRD1 complex interacts with the CC ERAD substrates HMG1 and HMG2 (PubMed:11390656). Interacts with KAR2 CC (PubMed:16873065). {ECO:0000269|PubMed:11018054, CC ECO:0000269|PubMed:11390656, ECO:0000269|PubMed:16619026, CC ECO:0000269|PubMed:16845381, ECO:0000269|PubMed:16873065, CC ECO:0000269|PubMed:16873066, ECO:0000269|PubMed:22262864, CC ECO:0000269|PubMed:28682307, ECO:0000269|PubMed:32327568}. CC -!- INTERACTION: CC Q05787; P25694: CDC48; NbExp=6; IntAct=EBI-31647, EBI-4308; CC Q05787; P38307: DER1; NbExp=3; IntAct=EBI-31647, EBI-5761; CC Q05787; Q08109: HRD1; NbExp=11; IntAct=EBI-31647, EBI-37613; CC Q05787; P00729: PRC1; NbExp=6; IntAct=EBI-31647, EBI-4153; CC Q05787; P32915: SEC61; NbExp=2; IntAct=EBI-31647, EBI-16400; CC Q05787; Q99220: YOS9; NbExp=8; IntAct=EBI-31647, EBI-34938; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305}; CC Single-pass membrane protein {ECO:0000305}. CC -!- SIMILARITY: Belongs to the sel-1 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U14913; AAB67427.1; -; Genomic_DNA. DR EMBL; BK006945; DAA09524.1; -; Genomic_DNA. DR PIR; S48558; S48558. DR RefSeq; NP_013308.1; NM_001182094.1. DR PDB; 5V7V; EM; 3.90 A; A=1-767. DR PDB; 6VJY; EM; 4.30 A; A=1-767. DR PDB; 6VJZ; EM; 4.30 A; A=1-767. DR PDB; 6VK0; EM; 4.10 A; A=1-767. DR PDB; 6VK1; EM; 3.90 A; A=1-767. DR PDB; 6VK3; EM; 3.70 A; A=1-767. DR PDBsum; 5V7V; -. DR PDBsum; 6VJY; -. DR PDBsum; 6VJZ; -. DR PDBsum; 6VK0; -. DR PDBsum; 6VK1; -. DR PDBsum; 6VK3; -. DR AlphaFoldDB; Q05787; -. DR EMDB; EMD-21220; -. DR EMDB; EMD-21221; -. DR EMDB; EMD-21222; -. DR EMDB; EMD-21223; -. DR EMDB; EMD-21224; -. DR EMDB; EMD-8638; -. DR EMDB; EMD-8639; -. DR EMDB; EMD-8642; -. DR SMR; Q05787; -. DR BioGRID; 31475; 124. DR ComplexPortal; CPX-1280; Luminal surveillance complex. DR ComplexPortal; CPX-3070; HRD1 E3 ubiquitin ligase complex. DR DIP; DIP-2843N; -. DR IntAct; Q05787; 13. DR MINT; Q05787; -. DR STRING; 4932.YLR207W; -. DR TCDB; 3.A.16.1.2; the endoplasmic reticular retrotranslocon (er-rt) family. DR GlyCosmos; Q05787; 5 sites, No reported glycans. DR GlyGen; Q05787; 5 sites. DR iPTMnet; Q05787; -. DR MaxQB; Q05787; -. DR PaxDb; 4932-YLR207W; -. DR PeptideAtlas; Q05787; -. DR EnsemblFungi; YLR207W_mRNA; YLR207W; YLR207W. DR GeneID; 850904; -. DR KEGG; sce:YLR207W; -. DR AGR; SGD:S000004197; -. DR SGD; S000004197; HRD3. DR VEuPathDB; FungiDB:YLR207W; -. DR eggNOG; KOG1550; Eukaryota. DR GeneTree; ENSGT00940000175926; -. DR HOGENOM; CLU_348239_0_0_1; -. DR InParanoid; Q05787; -. DR OMA; DMLAKPR; -. DR OrthoDB; 1378605at2759; -. DR BioCyc; YEAST:G3O-32325-MONOMER; -. DR BioGRID-ORCS; 850904; 5 hits in 10 CRISPR screens. DR PRO; PR:Q05787; -. DR Proteomes; UP000002311; Chromosome XII. DR RNAct; Q05787; Protein. DR GO; GO:0005783; C:endoplasmic reticulum; HDA:SGD. DR GO; GO:0005789; C:endoplasmic reticulum membrane; IPI:SGD. DR GO; GO:0000836; C:Hrd1p ubiquitin ligase complex; IPI:ComplexPortal. DR GO; GO:0000839; C:Hrd1p ubiquitin ligase ERAD-L complex; IDA:SGD. DR GO; GO:0000838; C:Hrd1p ubiquitin ligase ERAD-M complex; IDA:SGD. DR GO; GO:0034099; C:luminal surveillance complex; IDA:SGD. DR GO; GO:0002235; P:detection of unfolded protein; NAS:ComplexPortal. DR GO; GO:1905524; P:negative regulation of protein autoubiquitination; IDA:SGD. DR GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IMP:SGD. DR GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; IDA:SGD. DR GO; GO:0097466; P:ubiquitin-dependent glycoprotein ERAD pathway; NAS:ComplexPortal. DR Gene3D; 1.25.40.10; Tetratricopeptide repeat domain; 2. DR InterPro; IPR006597; Sel1-like. DR InterPro; IPR011990; TPR-like_helical_dom_sf. DR PANTHER; PTHR11102:SF147; FIBRONECTIN TYPE-II DOMAIN-CONTAINING PROTEIN; 1. DR PANTHER; PTHR11102; SEL-1-LIKE PROTEIN; 1. DR Pfam; PF08238; Sel1; 6. DR SMART; SM00671; SEL1; 6. DR SUPFAM; SSF81901; HCP-like; 3. PE 1: Evidence at protein level; KW 3D-structure; Endoplasmic reticulum; Glycoprotein; Membrane; KW Reference proteome; Repeat; Signal; Transmembrane; Transmembrane helix. FT SIGNAL 1..20 FT /evidence="ECO:0000255" FT CHAIN 21..833 FT /note="ERAD-associated E3 ubiquitin-protein ligase FT component HRD3" FT /id="PRO_0000240369" FT TRANSMEM 768..788 FT /note="Helical" FT /evidence="ECO:0000255" FT REPEAT 103..139 FT /note="Sel1-like 1" FT REPEAT 143..186 FT /note="Sel1-like 2" FT REPEAT 187..222 FT /note="Sel1-like 3" FT REPEAT 413..445 FT /note="Sel1-like 4" FT REPEAT 552..595 FT /note="Sel1-like 5" FT REPEAT 596..627 FT /note="Sel1-like 6" FT REPEAT 628..663 FT /note="Sel1-like 7" FT REGION 805..824 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT COMPBIAS 805..823 FT /note="Polar residues" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 101 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 123 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 142 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 429 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT CARBOHYD 611 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" SQ SEQUENCE 833 AA; 95481 MW; E7DB29FBA16D9BFD CRC64; MITLLLYLCV ICNAIVLIRA DSIADPWPEA RHLLNTIAKS RDPMKEAAME PNADEFVGFY VPMDYSPRNE EKNYQSIWQN EITDSQRHIY ELLVQSSEQF NNSEATYTLS QIHLWSQYNF PHNMTLAHKY LEKFNDLTHF TNHSAIFDLA VMYATGGCAS GNDQTVIPQD SAKALLYYQR AAQLGNLKAK QVLAYKYYSG FNVPRNFHKS LVLYRDIAEQ LRKSYSRDEW DIVFPYWESY NVRISDFESG LLGKGLNSVP SSTVRKRTTR PDIGSPFIAQ VNGVQMTLQI EPMGRFAFNG NDGNINGDED DEDASERRII RIYYAALNDY KGTYSQSRNC ERAKNLLELT YKEFQPHVDN LDPLQVFYYV RCLQLLGHMY FTGEGSSKPN IHMAEEILTT SLEISRRAQG PIGRACIDLG LINQYITNNI SQAISYYMKA MKTQANNGIV EFQLSKLATS FPEEKIGDPF NLMETAYLNG FIPAIYEFAV MIESGMNSKS SVENTAYLFK TFVDKNEAIM APKLRTAFAA LINDRSEVAL WAYSQLAEQG YETAQVSAAY LMYQLPYEFE DPPRTTDQRK TLAISYYTRA FKQGNIDAGV VAGDIYFQMQ NYSKAMALYQ GAALKYSIQA IWNLGYMHEH GLGVNRDFHL AKRYYDQVSE HDHRFYLASK LSVLKLHLKS WLTWITREKV NYWKPSSPLN PNEDTQHSKT SWYKQLTKIL QRMRHKEDSD KAAEDSHKHR TVVQNGANHR GDDQEEASEI LGFQMEDLVT MGCILGIFLL SILMSTLAAR RGWNVRFNGA QLNANGNRQQ EQQQQQQAQG PPGWDFNVQI FAI //