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DER1_YEAST
ID   DER1_YEAST              Reviewed;         211 AA.
AC   P38307; D6VQJ8;
DT   01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT   05-OCT-2010, sequence version 3.
DT   03-AUG-2022, entry version 162.
DE   RecName: Full=Degradation in the endoplasmic reticulum protein 1;
GN   Name=DER1; OrderedLocusNames=YBR201W; ORFNames=YBR1413;
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 [GENOMIC DNA], FUNCTION, AND SUBCELLULAR LOCATION.
RX   PubMed=8631297; DOI=10.1002/j.1460-2075.1996.tb00411.x;
RA   Knop M., Finger A., Braun T., Hellmuth K., Wolf D.H.;
RT   "Der1, a novel protein specifically required for endoplasmic reticulum
RT   degradation in yeast.";
RL   EMBO J. 15:753-763(1996).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=7975899; DOI=10.1002/yea.320100612;
RA   Mallet L., Bussereau F., Jacquet M.;
RT   "Nucleotide sequence analysis of an 11.7 kb fragment of yeast chromosome II
RT   including BEM1, a new gene of the WD-40 repeat family and a new member of
RT   the KRE2/MNT1 family.";
RL   Yeast 10:819-831(1994).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=7813418; DOI=10.1002/j.1460-2075.1994.tb06923.x;
RA   Feldmann H., Aigle M., Aljinovic G., Andre B., Baclet M.C., Barthe C.,
RA   Baur A., Becam A.-M., Biteau N., Boles E., Brandt T., Brendel M.,
RA   Brueckner M., Bussereau F., Christiansen C., Contreras R., Crouzet M.,
RA   Cziepluch C., Demolis N., Delaveau T., Doignon F., Domdey H.,
RA   Duesterhus S., Dubois E., Dujon B., El Bakkoury M., Entian K.-D.,
RA   Feuermann M., Fiers W., Fobo G.M., Fritz C., Gassenhuber J., Glansdorff N.,
RA   Goffeau A., Grivell L.A., de Haan M., Hein C., Herbert C.J.,
RA   Hollenberg C.P., Holmstroem K., Jacq C., Jacquet M., Jauniaux J.-C.,
RA   Jonniaux J.-L., Kallesoee T., Kiesau P., Kirchrath L., Koetter P.,
RA   Korol S., Liebl S., Logghe M., Lohan A.J.E., Louis E.J., Li Z.Y.,
RA   Maat M.J., Mallet L., Mannhaupt G., Messenguy F., Miosga T., Molemans F.,
RA   Mueller S., Nasr F., Obermaier B., Perea J., Pierard A., Piravandi E.,
RA   Pohl F.M., Pohl T.M., Potier S., Proft M., Purnelle B., Ramezani Rad M.,
RA   Rieger M., Rose M., Schaaff-Gerstenschlaeger I., Scherens B.,
RA   Schwarzlose C., Skala J., Slonimski P.P., Smits P.H.M., Souciet J.-L.,
RA   Steensma H.Y., Stucka R., Urrestarazu L.A., van der Aart Q.J.M.,
RA   Van Dyck L., Vassarotti A., Vetter I., Vierendeels F., Vissers S.,
RA   Wagner G., de Wergifosse P., Wolfe K.H., Zagulski M., Zimmermann F.K.,
RA   Mewes H.-W., Kleine K.;
RT   "Complete DNA sequence of yeast chromosome II.";
RL   EMBO J. 13:5795-5809(1994).
RN   [4]
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   [5]
RP   INDUCTION.
RX   PubMed=10847680; DOI=10.1016/s0092-8674(00)80835-1;
RA   Travers K.J., Patil C.K., Wodicka L., Lockhart D.J., Weissman J.S.,
RA   Walter P.;
RT   "Functional and genomic analyses reveal an essential coordination between
RT   the unfolded protein response and ER-associated degradation.";
RL   Cell 101:249-258(2000).
RN   [6]
RP   LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
RX   PubMed=14562106; DOI=10.1038/nature02046;
RA   Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N.,
RA   O'Shea E.K., Weissman J.S.;
RT   "Global analysis of protein expression in yeast.";
RL   Nature 425:737-741(2003).
RN   [7]
RP   MEMBRANE TOPOLOGY, AND MUTANT DER1-2.
RX   PubMed=15093775; DOI=10.1016/j.femsyr.2004.02.003;
RA   Hitt R., Wolf D.H.;
RT   "Der1p, a protein required for degradation of malfolded soluble proteins of
RT   the endoplasmic reticulum: topology and Der1-like proteins.";
RL   FEMS Yeast Res. 4:721-729(2004).
RN   [8]
RP   FUNCTION, IDENTIFICATION IN THE HRD1 COMPLEX, AND DISRUPTION PHENOTYPE.
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   [9]
RP   TOPOLOGY [LARGE SCALE ANALYSIS].
RC   STRAIN=ATCC 208353 / W303-1A;
RX   PubMed=16847258; DOI=10.1073/pnas.0604075103;
RA   Kim H., Melen K., Oesterberg M., von Heijne G.;
RT   "A global topology map of the Saccharomyces cerevisiae membrane proteome.";
RL   Proc. Natl. Acad. Sci. U.S.A. 103:11142-11147(2006).
RN   [10]
RP   FUNCTION, DISRUPTION PHENOTYPE, AND INTERACTION WITH USA1.
RX   PubMed=20005842; DOI=10.1016/j.molcel.2009.10.015;
RA   Horn S.C., Hanna J., Hirsch C., Volkwein C., Schutz A., Heinemann U.,
RA   Sommer T., Jarosch E.;
RT   "Usa1 functions as a scaffold of the HRD-ubiquitin ligase.";
RL   Mol. Cell 36:782-793(2009).
RN   [11]
RP   FUNCTION, DISRUPTION PHENOTYPE, ACETYLATION AT MET-1, AND MUTAGENESIS OF
RP   ASP-2.
RX   PubMed=23363603; DOI=10.1091/mbc.e12-11-0838;
RA   Zattas D., Adle D.J., Rubenstein E.M., Hochstrasser M.;
RT   "N-terminal acetylation of the yeast Derlin Der1 is essential for Hrd1
RT   ubiquitin-ligase activity toward luminal ER substrates.";
RL   Mol. Biol. Cell 24:890-900(2013).
RN   [12] {ECO:0007744|PDB:6VJZ, ECO:0007744|PDB:6VK0}
RP   STRUCTURE BY ELECTRON MICROSCOPY (4.10 ANGSTROMS) IN COMPLEX WITH HRD1;
RP   HRD3 AND USA1, FUNCTION, SUBUNIT, INTERACTION WITH USA1, TRANSMEMBRANE
RP   DOMAINS, AND MUTAGENESIS OF 79-ASN--THR-83.
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-associated degradation
CC       (ERAD) pathway. Specifically required for the ERAD-L pathway which
CC       mediates the degradation of proteins with misfolded lumenal domains
CC       within the endoplasmic reticulum (ER). Facilitates retrotranslocation
CC       of misfolded proteins from the ER lumen through the ER membrane in
CC       conjunction with HRD1 (PubMed:32327568). Both proteins have lateral
CC       gates facing each other and 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). {ECO:0000269|PubMed:16873066,
CC       ECO:0000269|PubMed:20005842, ECO:0000269|PubMed:23363603,
CC       ECO:0000269|PubMed:32327568, ECO:0000269|PubMed:8631297}.
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:16873066,
CC       PubMed:32327568). Within the complex, interacts with USA1 (via C-
CC       terminus) (PubMed:20005842, PubMed:32327568). In ERAD-L, HRD3 and YOS9
CC       jointly bind misfolded glycoproteins in the endoplasmic reticulum (ER)
CC       lumen (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). {ECO:0000269|PubMed:16873066,
CC       ECO:0000269|PubMed:20005842, ECO:0000269|PubMed:32327568}.
CC   -!- INTERACTION:
CC       P38307; P25694: CDC48; NbExp=5; IntAct=EBI-5761, EBI-4308;
CC       P38307; Q08109: HRD1; NbExp=5; IntAct=EBI-5761, EBI-37613;
CC       P38307; Q05787: HRD3; NbExp=3; IntAct=EBI-5761, EBI-31647;
CC       P38307; P00729: PRC1; NbExp=2; IntAct=EBI-5761, EBI-4153;
CC       P38307; P53044: UFD1; NbExp=3; IntAct=EBI-5761, EBI-19997;
CC       P38307; Q03714: USA1; NbExp=3; IntAct=EBI-5761, EBI-27760;
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000269|PubMed:8631297}; Multi-pass membrane protein
CC       {ECO:0000269|PubMed:8631297}.
CC   -!- INDUCTION: Up-regulated by the unfolded protein response (UPR).
CC       {ECO:0000269|PubMed:10847680}.
CC   -!- PTM: N-terminally acetylated by acetyltransferase NatB which enhances
CC       DER1 stability and is required for ERAD-L function.
CC       {ECO:0000269|PubMed:23363603}.
CC   -!- DISRUPTION PHENOTYPE: Impaired degradation of proteins with misfolded
CC       lumenal domains such as CPY*, a mutant, misfolded form of
CC       carboxypeptidase Y which is a known ERAD-L substrate. Degradation of
CC       proteins with misfolded intramembrane domains is not affected.
CC       {ECO:0000269|PubMed:16873066, ECO:0000269|PubMed:20005842,
CC       ECO:0000269|PubMed:23363603}.
CC   -!- MISCELLANEOUS: Present with 238 molecules/cell in log phase SD medium.
CC       {ECO:0000269|PubMed:14562106}.
CC   -!- SIMILARITY: Belongs to the derlin family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=CAA79688.1; Type=Frameshift; Evidence={ECO:0000305};
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DR   EMBL; X92435; CAA63165.1; -; Genomic_DNA.
DR   EMBL; Z21487; CAA79688.1; ALT_FRAME; Genomic_DNA.
DR   EMBL; Z36069; CAA85164.1; -; Genomic_DNA.
DR   EMBL; Z36070; CAA85165.1; -; Genomic_DNA.
DR   EMBL; BK006936; DAA07318.1; -; Genomic_DNA.
DR   PIR; S45450; S45450.
DR   RefSeq; NP_009760.1; NM_001178549.1.
DR   PDB; 6VJZ; EM; 4.30 A; C=1-211.
DR   PDB; 6VK0; EM; 4.10 A; C=1-211.
DR   PDBsum; 6VJZ; -.
DR   PDBsum; 6VK0; -.
DR   AlphaFoldDB; P38307; -.
DR   SMR; P38307; -.
DR   BioGRID; 32898; 252.
DR   ComplexPortal; CPX-3070; HRD1 ubiquitin ligase complex.
DR   DIP; DIP-4767N; -.
DR   IntAct; P38307; 9.
DR   MINT; P38307; -.
DR   STRING; 4932.YBR201W; -.
DR   TCDB; 3.A.16.1.2; the endoplasmic reticular retrotranslocon (er-rt) family.
DR   iPTMnet; P38307; -.
DR   MaxQB; P38307; -.
DR   PaxDb; P38307; -.
DR   PRIDE; P38307; -.
DR   EnsemblFungi; YBR201W_mRNA; YBR201W; YBR201W.
DR   GeneID; 852500; -.
DR   KEGG; sce:YBR201W; -.
DR   SGD; S000000405; DER1.
DR   VEuPathDB; FungiDB:YBR201W; -.
DR   eggNOG; KOG0858; Eukaryota.
DR   HOGENOM; CLU_1256224_0_0_1; -.
DR   InParanoid; P38307; -.
DR   OMA; KKGQYER; -.
DR   BioCyc; YEAST:G3O-29142-MON; -.
DR   Reactome; R-SCE-5358346; Hedgehog ligand biogenesis.
DR   PRO; PR:P38307; -.
DR   Proteomes; UP000002311; Chromosome II.
DR   RNAct; P38307; protein.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IDA: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:0030176; C:integral component of endoplasmic reticulum membrane; IBA:GO_Central.
DR   GO; GO:0051787; F:misfolded protein binding; IDA:SGD.
DR   GO; GO:0030968; P:endoplasmic reticulum unfolded protein response; IBA:GO_Central.
DR   GO; GO:0070843; P:misfolded protein transport; IMP:SGD.
DR   GO; GO:0006515; P:protein quality control for misfolded or incompletely synthesized proteins; IMP:UniProtKB.
DR   GO; GO:0030970; P:retrograde protein transport, ER to cytosol; IMP:SGD.
DR   GO; GO:0030433; P:ubiquitin-dependent ERAD pathway; IMP:SGD.
DR   InterPro; IPR007599; DER1.
DR   Pfam; PF04511; DER1; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Endoplasmic reticulum; Membrane;
KW   Protein transport; Reference proteome; Transmembrane; Transmembrane helix;
KW   Transport.
FT   CHAIN           1..211
FT                   /note="Degradation in the endoplasmic reticulum protein 1"
FT                   /id="PRO_0000219053"
FT   TOPO_DOM        1..14
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TRANSMEM        15..32
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TOPO_DOM        33..67
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TRANSMEM        68..85
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TOPO_DOM        86..92
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TRANSMEM        93..109
FT                   /note="Helical; Name=3"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TOPO_DOM        110..117
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TRANSMEM        118..133
FT                   /note="Helical; Name=4"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TOPO_DOM        134..149
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TRANSMEM        150..165
FT                   /note="Helical; Name=5"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TOPO_DOM        166..168
FT                   /note="Lumenal"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TRANSMEM        169..189
FT                   /note="Helical; Name=6"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   TOPO_DOM        190..211
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine"
FT                   /evidence="ECO:0000269|PubMed:23363603"
FT   MUTAGEN         2
FT                   /note="D->A: Cleavage of initiator methionine, acetylation
FT                   of Ala-2 by NatA, slightly reduced acetylation levels but
FT                   no significant effect on endogenous stability or ability to
FT                   degrade CPY*."
FT                   /evidence="ECO:0000269|PubMed:23363603"
FT   MUTAGEN         2
FT                   /note="D->E: No effect on ability to degrade CPY*."
FT                   /evidence="ECO:0000269|PubMed:23363603"
FT   MUTAGEN         2
FT                   /note="D->K: N-terminus not predicted to be acetylated.
FT                   Strongly decreases endogenous stability."
FT                   /evidence="ECO:0000269|PubMed:23363603"
FT   MUTAGEN         2
FT                   /note="D->L: Predicted to lead to acetylation by NatC. No
FT                   effect on endogenous stability or ability to degrade CPY*."
FT                   /evidence="ECO:0000269|PubMed:23363603"
FT   MUTAGEN         59
FT                   /note="S->L: In der1-2; impairs the ability to degrade
FT                   misfolded proteins."
FT   MUTAGEN         79..83
FT                   /note="NHLST->LHLLV: Reduced ERAD-L degradation rate."
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   MUTAGEN         79..83
FT                   /note="NHLST->SHLKN: No effect on ERAD-L degradation rate."
FT                   /evidence="ECO:0000269|PubMed:32327568"
FT   CONFLICT        145
FT                   /note="A -> V (in Ref. 1; CAA63165)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   211 AA;  24391 MW;  41510999E92C691D CRC64;
     MDAVILNLLG DIPLVTRLWT IGCLVLSGLT SLRIVDPGKV VYSYDLVFKK GQYGRLLYSI
     FDYGAFNWIS MINIFVSANH LSTLENSFNL RRKFCWIIFL LLVILVKMTS IEQPAASLGV
     LLHENLVYYE LKKNGNQMNV RFFGAIDVSP SIFPIYMNAV MYFVYKRSWL EIAMNFMPGH
     VIYYMDDIIG KIYGIDLCKS PYDWFRNTET P
 
 
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