ID   VHL_CANLF               Reviewed;         219 AA.
AC   Q5Q9Z2;
DT   26-APR-2005, integrated into UniProtKB/Swiss-Prot.
DT   04-JAN-2005, sequence version 1.
DT   25-MAY-2022, entry version 99.
DE   RecName: Full=von Hippel-Lindau disease tumor suppressor;
DE   AltName: Full=pVHL;
GN   Name=VHL;
OS   Canis lupus familiaris (Dog) (Canis familiaris).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Carnivora; Caniformia; Canidae; Canis.
OX   NCBI_TaxID=9615;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Kobayashi N., Sato T., Shibuya H., Suzuki K.;
RT   "cDNA sequence of canine von Hippel-Lindau disease tumor suppressor gene.";
RL   Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases.
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 (By similarity).
CC       {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 (By similarity). 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   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250}. Membrane {ECO:0000250};
CC       Peripheral membrane protein {ECO:0000250}. Nucleus {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; AY764285; AAV68308.1; -; mRNA.
DR   RefSeq; NP_001008552.1; NM_001008552.1.
DR   AlphaFoldDB; Q5Q9Z2; -.
DR   SMR; Q5Q9Z2; -.
DR   STRING; 9615.ENSCAFP00000007687; -.
DR   PRIDE; Q5Q9Z2; -.
DR   GeneID; 494000; -.
DR   KEGG; cfa:494000; -.
DR   CTD; 7428; -.
DR   InParanoid; Q5Q9Z2; -.
DR   OrthoDB; 1509532at2759; -.
DR   UniPathway; UPA00143; -.
DR   Proteomes; UP000002254; Unplaced.
DR   GO; GO:0016020; C:membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR   GO; GO:0030891; C:VCB complex; IBA:GO_Central.
DR   GO; GO:0016567; P:protein ubiquitination; IBA:GO_Central.
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   2: Evidence at transcript level;
KW   Cytoplasm; Membrane; Nucleus; Reference proteome; Tumor suppressor;
KW   Ubl conjugation pathway.
FT   CHAIN           1..219
FT                   /note="von Hippel-Lindau disease tumor suppressor"
FT                   /id="PRO_0000065808"
FT   REGION          1..57
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          157..166
FT                   /note="Interaction with Elongin BC complex"
FT                   /evidence="ECO:0000250"
FT   COMPBIAS        14..49
FT                   /note="Acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
SQ   SEQUENCE   219 AA;  24467 MW;  97E188260FB5C826 CRC64;
     MPRKAGSVEE AEAGAEEVGA EEVGPEESGG EESGAEESGP EESDPEEPGA AAEMEAGQPR
     PVLRSVNSCE PSQVIFCNRS PRVVLPVWLN FDGEPQPYPT LPPGTGRRIH SYRGHLWLFR
     DAGTYDGLLV NQTELFVPSL NVDGQPIFAN ITLPVYTLKE RCLQVVRSLV KPENYRRLDI
     VRSLYEDLED HPNVRKDLER LAQEHIENQR MEGETEDFN