ID   VHL_RAT                 Reviewed;         185 AA.
AC   Q64259; Q64197; Q80WY8;
DT   03-JUL-2003, integrated into UniProtKB/Swiss-Prot.
DT   01-NOV-1996, sequence version 1.
DT   03-AUG-2022, entry version 165.
DE   RecName: Full=von Hippel-Lindau disease tumor suppressor;
DE   AltName: Full=pVHL;
GN   Name=Vhl;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=7604013; DOI=10.1073/pnas.92.14.6459;
RA   Duan D.R., Humphrey J.S., Chen D.Y., Weng Y., Sukegawa J., Lee S.,
RA   Gnarra J.R., Linehan W.M., Klausner R.D.;
RT   "Characterization of the VHL tumor suppressor gene product: localization,
RT   complex formation, and the effect of natural inactivating mutations.";
RL   Proc. Natl. Acad. Sci. U.S.A. 92:6459-6463(1995).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=7493907; DOI=10.1111/j.1349-7006.1995.tb02999.x;
RA   Kikuchi Y., Kobayashi E., Nishizawa M., Hamazaki S., Okada S., Hino O.;
RT   "Cloning of the rat homologue of the von Hippel-Lindau tumor suppressor
RT   gene and its non-somatic mutation in rat renal cell carcinomas.";
RL   Jpn. J. Cancer Res. 86:905-909(1995).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 31-153.
RX   PubMed=8599582;
RX   DOI=10.1002/(sici)1098-2744(199602)15:2<154::aid-mc8>3.0.co;2-j;
RA   Walker C., Ahn Y.T., Everitt J., Yuan X.;
RT   "Renal cell carcinoma development in the rat independent of alterations at
RT   the VHL gene locus.";
RL   Mol. Carcinog. 15:154-161(1996).
RN   [4]
RP   INTERACTION WITH CARD9.
RX   PubMed=17936701; DOI=10.1016/j.molcel.2007.09.010;
RA   Yang H., Minamishima Y.A., Yan Q., Schlisio S., Ebert B.L., Zhang X.,
RA   Zhang L., Kim W.Y., Olumi A.F., Kaelin W.G. Jr.;
RT   "pVHL acts as an adaptor to promote the inhibitory phosphorylation of the
RT   NF-kappaB agonist Card9 by CK2.";
RL   Mol. Cell 28:15-27(2007).
CC   -!- FUNCTION: Involved in the ubiquitination and subsequent proteasomal
CC       degradation via the von Hippel-Lindau ubiquitination complex. Seems to
CC       act as a target recruitment subunit in the E3 ubiquitin ligase complex
CC       and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic
CC       conditions. Involved in transcriptional repression through interaction
CC       with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an
CC       oxygen-responsive manner, ADRB2 (By similarity). {ECO:0000250}.
CC   -!- PATHWAY: Protein modification; protein ubiquitination.
CC   -!- SUBUNIT: Component of the VBC (VHL-Elongin BC-CUL2) complex; this
CC       complex acts as a ubiquitin-ligase E3 and directs proteasome-dependent
CC       degradation of targeted proteins. Interacts with CUL2; this interaction
CC       is dependent on the integrity of the trimeric VBC complex. Interacts
CC       (via the beta domain) with HIF1A (via the NTAD domain); this
CC       interaction mediates degradation of HIF1A in normoxia and, in hypoxia,
CC       prevents ubiquitination and degradation of HIF1A by mediating hypoxia-
CC       induced translocation to the nucleus, a process which requires a
CC       hypoxia-dependent regulatory signal. Interacts with ADRB2; the
CC       interaction, in normoxia, is dependent on hydroxylation of ADRB2 and
CC       the subsequent VCB-mediated ubiquitination and degradation of ADRB2.
CC       Under hypoxia, hydroxylation, interaction with VHL, ubiquitination and
CC       subsequent degradation of ADRB2 are dramatically decreased. Interacts
CC       with RNF139, USP33 and JADE1 (By similarity). Found in a complex
CC       composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Interacts with LIMD1
CC       (via LIM zinc-binding 2). Interacts with AJUBA (via LIM domains) and
CC       WTIP (via LIM domains) (By similarity). Interacts with EPAS1. Interacts
CC       with CARD9 (PubMed:17936701). Interacts with DCUN1D1 independently of
CC       CUL2; this interaction engages DCUN1D1 in the VCB complex and triggers
CC       CUL2 neddylation and consequently cullin ring ligase (CRL) substrates
CC       polyubiquitylation (By similarity). Interacts with ALAS1 (hydroxylated
CC       form) (By similarity). {ECO:0000250|UniProtKB:P40337,
CC       ECO:0000269|PubMed:17936701}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000250};
CC       Peripheral membrane protein {ECO:0000250}. Nucleus {ECO:0000250}.
CC       Note=Colocalizes with ADRB2 at the cell membrane. {ECO:0000250}.
CC   -!- DOMAIN: The Elongin BC complex binding domain is also known as BC-box
CC       with the consensus [APST]-L-x(3)-C-x(3)-[AILV].
CC   -!- SIMILARITY: Belongs to the VHL family. {ECO:0000305}.
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DR   EMBL; U14746; AAA86874.1; -; mRNA.
DR   EMBL; S80345; AAB35675.1; -; mRNA.
DR   EMBL; S81658; AAP32238.1; -; mRNA.
DR   PIR; T10752; T10752.
DR   RefSeq; NP_434688.1; NM_052801.1.
DR   AlphaFoldDB; Q64259; -.
DR   SMR; Q64259; -.
DR   BioGRID; 246987; 7.
DR   CORUM; Q64259; -.
DR   STRING; 10116.ENSRNOP00000013727; -.
DR   PaxDb; Q64259; -.
DR   Ensembl; ENSRNOT00000013727; ENSRNOP00000013727; ENSRNOG00000010258.
DR   GeneID; 24874; -.
DR   KEGG; rno:24874; -.
DR   UCSC; RGD:3960; rat.
DR   CTD; 7428; -.
DR   RGD; 3960; Vhl.
DR   eggNOG; KOG4710; Eukaryota.
DR   GeneTree; ENSGT00390000014353; -.
DR   HOGENOM; CLU_116090_0_0_1; -.
DR   InParanoid; Q64259; -.
DR   OMA; VGHPWLF; -.
DR   OrthoDB; 1509532at2759; -.
DR   PhylomeDB; Q64259; -.
DR   TreeFam; TF318985; -.
DR   Reactome; R-RNO-1234176; Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
DR   Reactome; R-RNO-3232142; SUMOylation of ubiquitinylation proteins.
DR   Reactome; R-RNO-8951664; Neddylation.
DR   Reactome; R-RNO-9706019; RHOBTB3 ATPase cycle.
DR   Reactome; R-RNO-983168; Antigen processing: Ubiquitination & Proteasome degradation.
DR   UniPathway; UPA00143; -.
DR   PRO; PR:Q64259; -.
DR   Proteomes; UP000002494; Chromosome 4.
DR   Bgee; ENSRNOG00000010258; Expressed in jejunum and 20 other tissues.
DR   Genevisible; Q64259; RN.
DR   GO; GO:0005929; C:cilium; ISO:RGD.
DR   GO; GO:0031462; C:Cul2-RING ubiquitin ligase complex; ISO:RGD.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; IDA:RGD.
DR   GO; GO:0098978; C:glutamatergic synapse; ISO:RGD.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005739; C:mitochondrion; IDA:RGD.
DR   GO; GO:0005730; C:nucleolus; ISO:RGD.
DR   GO; GO:0005654; C:nucleoplasm; ISO:RGD.
DR   GO; GO:0005634; C:nucleus; IDA:RGD.
DR   GO; GO:0098794; C:postsynapse; IEA:GOC.
DR   GO; GO:0005667; C:transcription regulator complex; TAS:RGD.
DR   GO; GO:0030891; C:VCB complex; IDA:RGD.
DR   GO; GO:0140297; F:DNA-binding transcription factor binding; ISO:RGD.
DR   GO; GO:0019899; F:enzyme binding; ISO:RGD.
DR   GO; GO:0044877; F:protein-containing complex binding; IPI:RGD.
DR   GO; GO:0003711; F:transcription elongation regulator activity; ISO:RGD.
DR   GO; GO:1990756; F:ubiquitin ligase-substrate adaptor activity; ISO:RGD.
DR   GO; GO:0001525; P:angiogenesis; ISO:RGD.
DR   GO; GO:0043534; P:blood vessel endothelial cell migration; ISO:RGD.
DR   GO; GO:0048593; P:camera-type eye morphogenesis; ISO:RGD.
DR   GO; GO:0061073; P:ciliary body morphogenesis; ISO:RGD.
DR   GO; GO:0045446; P:endothelial cell differentiation; IEA:Ensembl.
DR   GO; GO:0030198; P:extracellular matrix organization; ISO:RGD.
DR   GO; GO:0048069; P:eye pigmentation; ISO:RGD.
DR   GO; GO:0048877; P:homeostasis of number of retina cells; ISO:RGD.
DR   GO; GO:0097411; P:hypoxia-inducible factor-1alpha signaling pathway; IEA:Ensembl.
DR   GO; GO:0061072; P:iris morphogenesis; ISO:RGD.
DR   GO; GO:0006582; P:melanin metabolic process; ISO:RGD.
DR   GO; GO:0008285; P:negative regulation of cell population proliferation; ISO:RGD.
DR   GO; GO:0045602; P:negative regulation of endothelial cell differentiation; ISO:RGD.
DR   GO; GO:0010629; P:negative regulation of gene expression; ISO:RGD.
DR   GO; GO:1902072; P:negative regulation of hypoxia-inducible factor-1alpha signaling pathway; ISO:RGD.
DR   GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; ISO:RGD.
DR   GO; GO:0070244; P:negative regulation of thymocyte apoptotic process; ISO:RGD.
DR   GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:RGD.
DR   GO; GO:0034244; P:negative regulation of transcription elongation from RNA polymerase II promoter; ISO:RGD.
DR   GO; GO:0061428; P:negative regulation of transcription from RNA polymerase II promoter in response to hypoxia; ISO:RGD.
DR   GO; GO:0030182; P:neuron differentiation; IDA:RGD.
DR   GO; GO:0003310; P:pancreatic A cell differentiation; ISO:RGD.
DR   GO; GO:0050679; P:positive regulation of epithelial cell proliferation; ISO:RGD.
DR   GO; GO:0045893; P:positive regulation of transcription, DNA-templated; ISO:RGD.
DR   GO; GO:0010498; P:proteasomal protein catabolic process; ISO:RGD.
DR   GO; GO:0030163; P:protein catabolic process; ISO:RGD.
DR   GO; GO:0015031; P:protein transport; ISO:RGD.
DR   GO; GO:0016567; P:protein ubiquitination; ISO:RGD.
DR   GO; GO:2001233; P:regulation of apoptotic signaling pathway; ISO:RGD.
DR   GO; GO:0042069; P:regulation of catecholamine metabolic process; IMP:RGD.
DR   GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR   GO; GO:0099175; P:regulation of postsynapse organization; ISO:RGD.
DR   GO; GO:0099576; P:regulation of protein catabolic process at postsynapse, modulating synaptic transmission; ISO:RGD.
DR   GO; GO:0032880; P:regulation of protein localization; ISO:RGD.
DR   GO; GO:0070243; P:regulation of thymocyte apoptotic process; ISO:RGD.
DR   GO; GO:0006355; P:regulation of transcription, DNA-templated; IDA:RGD.
DR   GO; GO:0045471; P:response to ethanol; IEP:RGD.
DR   GO; GO:0001666; P:response to hypoxia; IMP:RGD.
DR   GO; GO:0003309; P:type B pancreatic cell differentiation; ISO:RGD.
DR   CDD; cd05468; pVHL; 1.
DR   Gene3D; 1.10.750.10; -; 1.
DR   Gene3D; 2.60.40.780; -; 1.
DR   InterPro; IPR002714; VHL.
DR   InterPro; IPR024048; VHL_alpha_dom.
DR   InterPro; IPR037139; VHL_alpha_dom_sf.
DR   InterPro; IPR024053; VHL_beta_dom.
DR   InterPro; IPR037140; VHL_beta_dom_sf.
DR   InterPro; IPR036208; VHL_sf.
DR   InterPro; IPR022772; VHL_tumour_suppress_b/a_dom.
DR   PANTHER; PTHR15160:SF10; PTHR15160:SF10; 1.
DR   Pfam; PF01847; VHL; 1.
DR   Pfam; PF17211; VHL_C; 1.
DR   SUPFAM; SSF49468; SSF49468; 1.
PE   1: Evidence at protein level;
KW   Cytoplasm; Membrane; Nucleus; Reference proteome; Tumor suppressor;
KW   Ubl conjugation pathway.
FT   CHAIN           1..185
FT                   /note="von Hippel-Lindau disease tumor suppressor"
FT                   /id="PRO_0000065811"
FT   REGION          1..29
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          123..132
FT                   /note="Interaction with Elongin BC complex"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        1..25
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ   SEQUENCE   185 AA;  21215 MW;  3AD15FD9EF139E13 CRC64;
     MPRKAASPEE AERMPGSEEI EAGRPRPVLR SVNSREPSQV IFCNRSPRVV LPLWLNFDGE
     PQPYPTLPPG TGRRIHSYRG HLWLFRDAGT HDGLLVNQTE LFVPSLNVDG QPIFANITLP
     VYTLKERCLQ VVRSLVKPEN YRRLDIVRSL YEDLEDHPNV RKDIQRLTQE HLENQALGEE
     PEGVH