HRD3_YEAST
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 03-AUG-2022, entry version 161.
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}.
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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 SMR; Q05787; -.
DR BioGRID; 31475; 116.
DR ComplexPortal; CPX-1280; Luminal surveillance complex.
DR ComplexPortal; CPX-3070; HRD1 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 iPTMnet; Q05787; -.
DR MaxQB; Q05787; -.
DR PaxDb; Q05787; -.
DR PRIDE; Q05787; -.
DR EnsemblFungi; YLR207W_mRNA; YLR207W; YLR207W.
DR GeneID; 850904; -.
DR KEGG; sce:YLR207W; -.
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 BioCyc; YEAST:G3O-32325-MON; -.
DR Reactome; R-SCE-5358346; Hedgehog ligand biogenesis.
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:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0034099; C:luminal surveillance complex; IDA:SGD.
DR GO; GO:0002235; P:detection of unfolded protein; IC:ComplexPortal.
DR GO; GO:0036503; P:ERAD pathway; IBA:GO_Central.
DR GO; GO:1905524; P:negative regulation of protein autoubiquitination; IDA:SGD.
DR GO; GO:0016567; P:protein ubiquitination; IEA:GOC.
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; IC:ComplexPortal.
DR Gene3D; 1.25.40.10; -; 2.
DR InterPro; IPR006597; Sel1-like.
DR InterPro; IPR011990; TPR-like_helical_dom_sf.
DR Pfam; PF08238; Sel1; 4.
DR SMART; SM00671; SEL1; 6.
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
