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UniProtKB - P40337 (VHL_HUMAN)

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Protein

Von Hippel-Lindau disease tumor suppressor

Gene

VHL

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as a target recruitment subunit in the E3 ubiquitin ligase complex and recruits hydroxylated hypoxia-inducible factor (HIF) under normoxic conditions. Involved in transcriptional repression through interaction with HIF1A, HIF1AN and histone deacetylases. Ubiquitinates, in an oxygen-responsive manner, ADRB2.3 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • transcription factor binding Source: UniProtKB
  • ubiquitin protein ligase activity Source: ParkinsonsUK-UCL
  • ubiquitin-protein transferase activity Source: Reactome
Complete GO annotation...

GO - Biological processi

  • cell morphogenesis Source: UniProtKB
  • negative regulation of apoptotic process Source: UniProtKB
  • negative regulation of cell proliferation Source: CAFA
  • negative regulation of gene expression Source: CAFA
  • negative regulation of JAK-STAT cascade Source: CAFA
  • negative regulation of transcription from RNA polymerase II promoter Source: ProtInc
  • negative regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: UniProtKB
  • positive regulation of cell differentiation Source: UniProtKB
  • positive regulation of transcription, DNA-templated Source: UniProtKB
  • post-translational protein modification Source: Reactome
  • protein stabilization Source: UniProtKB
  • protein ubiquitination Source: ParkinsonsUK-UCL
  • proteolysis Source: ProtInc
  • regulation of transcription, DNA-templated Source: BHF-UCL
  • regulation of transcription from RNA polymerase II promoter in response to hypoxia Source: Reactome
Complete GO annotation...

Keywordsi

Biological processUbl conjugation pathway

Enzyme and pathway databases

ReactomeiR-HSA-1234176. Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha.
R-HSA-8951664. Neddylation.
R-HSA-983168. Antigen processing: Ubiquitination & Proteasome degradation.
SIGNORiP40337.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
Von Hippel-Lindau disease tumor suppressor
Alternative name(s):
Protein G7
pVHL
Gene namesi
Name:VHL
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

HGNCiHGNC:12687. VHL.

Subcellular locationi

Isoform 1 :
Isoform 3 :
  • Cytoplasm
  • Nucleus

    • Note: Equally distributed between the nucleus and the cytoplasm but not membrane-associated.

GO - Cellular componenti

  • cytosol Source: Reactome
  • endoplasmic reticulum Source: UniProtKB
  • membrane Source: UniProtKB-SubCell
  • mitochondrion Source: UniProtKB
  • nucleoplasm Source: HPA
  • nucleus Source: ProtInc
  • VCB complex Source: GO_Central
Complete GO annotation...

Keywords - Cellular componenti

Cytoplasm, Membrane, Nucleus

Pathology & Biotechi

Involvement in diseasei

Pheochromocytoma (PCC)3 Publications
Disease susceptibility is associated with variations affecting the gene represented in this entry.
Disease descriptionA catecholamine-producing tumor of chromaffin tissue of the adrenal medulla or sympathetic paraganglia. The cardinal symptom, reflecting the increased secretion of epinephrine and norepinephrine, is hypertension, which may be persistent or intermittent.
See also OMIM:171300
von Hippel-Lindau disease (VHLD)18 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionVHLD is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign neoplasms, most frequently retinal, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. VHL type 1 is without pheochromocytoma, type 2 is with pheochromocytoma. VHL type 2 is further subdivided into types 2A (pheochromocytoma, retinal angioma, and hemangioblastomas without renal cell carcinoma and pancreatic cyst) and 2B (pheochromocytoma, retinal angioma, and hemangioblastomas with renal cell carcinoma and pancreatic cyst).
See also OMIM:193300
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_00567038S → P in VHLD; type II. 1 Publication1
Natural variantiVAR_00567152E → K in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs373068386Ensembl.1
Natural variantiVAR_00567265S → L in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030826Ensembl.1
Natural variantiVAR_00567365S → W in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030826Ensembl.1
Natural variantiVAR_00567466 – 73Missing in VHLD; type I. 8
Natural variantiVAR_00567568S → W in pheochromocytoma and VHLD; type II. 2 Publications1
Natural variantiVAR_00567670E → K in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030802Ensembl.1
Natural variantiVAR_00567774V → G in VHLD; type I-II. 1 PublicationCorresponds to variant dbSNP:rs5030803Ensembl.1
Natural variantiVAR_03499075Missing in VHLD. 1 Publication1
Natural variantiVAR_00567976F → I in VHLD; type I. 1 Publication1
Natural variantiVAR_00568076F → L in VHLD; type I. 1 Publication1
Natural variantiVAR_00568176F → S in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs730882033Ensembl.1
Natural variantiVAR_00567876Missing in VHLD; type I; common mutation. 1 Publication1
Natural variantiVAR_00568278N → H in VHLD; type I. 1 Publication1
Natural variantiVAR_00568378N → S in VHLD; type I; common mutation. 1 PublicationCorresponds to variant dbSNP:rs5030804Ensembl.1
Natural variantiVAR_00568478N → T in VHLD; type I. 1 Publication1
Natural variantiVAR_00568579R → P in VHLD. 1
Natural variantiVAR_00568680S → I in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030805Ensembl.1
Natural variantiVAR_00568880S → N in pheochromocytoma and VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs5030805Ensembl.1
Natural variantiVAR_00568780S → R in VHLD; type I. 2 Publications1
Natural variantiVAR_00568981P → S in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030806Ensembl.1
Natural variantiVAR_00569182 – 84Missing in VHLD. 3
Natural variantiVAR_00569082R → P in VHLD; type I. Corresponds to variant dbSNP:rs794726890Ensembl.1
Natural variantiVAR_00569284V → L in VHLD; type II and type 2C. 2 PublicationsCorresponds to variant dbSNP:rs5030827Ensembl.1
Natural variantiVAR_00569386P → A in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs398123481Ensembl.1
Natural variantiVAR_00809786P → H in VHLD. 1
Natural variantiVAR_00569486P → L in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs730882034Ensembl.1
Natural variantiVAR_00569586P → R in VHLD; type I. 1 Publication1
Natural variantiVAR_00569686P → S in VHLD. 2 PublicationsCorresponds to variant dbSNP:rs398123481Ensembl.1
Natural variantiVAR_00569788W → R in VHLD; type I. 2 Publications1
Natural variantiVAR_00569888W → S in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs119103277Ensembl.1
Natural variantiVAR_00570089L → P in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030807Ensembl.1
Natural variantiVAR_00570292 – 97Missing in VHLD; type I. 6
Natural variantiVAR_00570393G → C in pheochromocytoma and VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs5030808Ensembl.1
Natural variantiVAR_00570493G → D in VHLD. 1
Natural variantiVAR_00570593G → S in pheochromocytoma and VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs5030808Ensembl.1
Natural variantiVAR_00570696Q → P in VHLD; type I. 1 Publication1
Natural variantiVAR_00570798Y → H in pheochromocytoma and VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs5030809Ensembl.1
Natural variantiVAR_005708101L → G in VHLD; type I; requires 2 nucleotide substitutions. 1 Publication1
Natural variantiVAR_005709101L → R in VHLD; type I. 1 Publication1
Natural variantiVAR_005711105T → P in VHLD; type I. 1 Publication1
Natural variantiVAR_005713107R → P in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs193922609Ensembl.1
Natural variantiVAR_005714111S → C in VHLD; type II. 1
Natural variantiVAR_005715111S → N in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs869025631Ensembl.1
Natural variantiVAR_005716111S → R in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs765978945Ensembl.1
Natural variantiVAR_005717112Y → H in VHLD; type IIA. Corresponds to variant dbSNP:rs104893824Ensembl.1
Natural variantiVAR_034992112Y → N in VHLD. 1 PublicationCorresponds to variant dbSNP:rs104893824Ensembl.1
Natural variantiVAR_005718114G → C in VHLD; type II. 1 Publication1
Natural variantiVAR_005719114G → R in VHLD; type I-II. Corresponds to variant dbSNP:rs869025636Ensembl.1
Natural variantiVAR_005720114G → S in VHLD; type II. 1 Publication1
Natural variantiVAR_005723115H → Q in VHLD; type II. 1 Publication1
Natural variantiVAR_008098115H → R in VHLD; type II. Corresponds to variant dbSNP:rs5030812Ensembl.1
Natural variantiVAR_005722115H → Y in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030811Ensembl.1
Natural variantiVAR_005724116L → V in VHLD. 1 Publication1
Natural variantiVAR_005725117W → C in VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs727504215Ensembl.1
Natural variantiVAR_005726118L → P in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030830Ensembl.1
Natural variantiVAR_005727118L → R in VHLD. 1 Publication1
Natural variantiVAR_005728119F → L in pheochromocytoma and VHLD; type II. 1 Publication1
Natural variantiVAR_005729119F → S in VHLD; type II. 1 Publication1
Natural variantiVAR_005730121D → G in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030832Ensembl.1
Natural variantiVAR_005731128L → F in VHLD; type II. 1
Natural variantiVAR_005732129L → LE in VHLD. 1
Natural variantiVAR_005733130V → L in ECYT2 and VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs104893830Ensembl.1
Natural variantiVAR_005734131N → K in VHLD; type I. 1 Publication1
Natural variantiVAR_005735131N → T in VHLD; type I. 1 Publication1
Natural variantiVAR_005737136F → C in pheochromocytoma and VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs5030833Ensembl.1
Natural variantiVAR_005736136F → S in VHLD. 1 PublicationCorresponds to variant dbSNP:rs5030833Ensembl.1
Natural variantiVAR_008099136F → Y in VHLD. 1
Natural variantiVAR_005738143D → E in VHLD; type II. 1 Publication1
Natural variantiVAR_008100145Q → H in VHLD. Corresponds to variant dbSNP:rs771727849Ensembl.1
Natural variantiVAR_005739148Missing in VHLD; type I. 1
Natural variantiVAR_005740149A → T in VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs587780077Ensembl.1
Natural variantiVAR_005741154P → L in VHLD; type II. 1
Natural variantiVAR_005742155V → G in VHLD; type II. 1 Publication1
Natural variantiVAR_008101155V → M in VHLD; with RCC. Corresponds to variant dbSNP:rs869025659Ensembl.1
Natural variantiVAR_005743156Y → C in pheochromocytoma and VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs397516441Ensembl.1
Natural variantiVAR_005744156Y → D in VHLD; type I. 1 Publication1
Natural variantiVAR_005746157T → I in VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs869025660Ensembl.1
Natural variantiVAR_005747157T → TF in VHLD; type I. 1
Natural variantiVAR_005748158L → P in VHLD; type I-II; abolishes release from chaperonin complex and the interaction with Elongin BC complex. 3 PublicationsCorresponds to variant dbSNP:rs121913346Ensembl.1
Natural variantiVAR_005749158L → V in VHLD; type I. 1 Publication1
Natural variantiVAR_005750159K → E in VHLD; type II. 1
Natural variantiVAR_005753161R → G in VHLD; type II. Corresponds to variant dbSNP:rs5030818Ensembl.1
Natural variantiVAR_005752161R → P in pheochromocytoma and VHLD; type I. 2 Publications1
Natural variantiVAR_005751161R → Q in pheochromocytoma and VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs730882035Ensembl.1
Natural variantiVAR_005754162C → F in VHLD; type I; No effect on interaction with HIF1A nor on HIF1A degradation. 4 PublicationsCorresponds to variant dbSNP:rs397516444Ensembl.1
Natural variantiVAR_005755162C → R in VHLD; type I. 1 Publication1
Natural variantiVAR_005756162C → W in VHLD; type I-II. 2 Publications1
Natural variantiVAR_005757162C → Y in VHLD; type I. 1 Publication1
Natural variantiVAR_008102164Q → H in VHLD. 1
Natural variantiVAR_005758164Q → R in VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs267607170Ensembl.1
Natural variantiVAR_008103166V → D in VHLD; with RCC. 1
Natural variantiVAR_005759166V → F in VHLD; type IIA. 2 PublicationsCorresponds to variant dbSNP:rs104893825Ensembl.1
Natural variantiVAR_005760167R → G in VHLD; type I-II. 1 PublicationCorresponds to variant dbSNP:rs5030820Ensembl.1
Natural variantiVAR_005761167R → Q in pheochromocytoma and VHLD; type II; common mutation. 3 PublicationsCorresponds to variant dbSNP:rs5030821Ensembl.1
Natural variantiVAR_005762167R → W in pheochromocytoma and VHLD; type II; common mutation. 4 PublicationsCorresponds to variant dbSNP:rs5030820Ensembl.1
Natural variantiVAR_005763170V → D in VHLD; type II. 1 Publication1
Natural variantiVAR_005764170V → F in VHLD; type II. 1
Natural variantiVAR_005765170V → G in VHLD; type I. 2 Publications1
Natural variantiVAR_005766175Y → D in VHLD; type I. 1 Publication1
Natural variantiVAR_008104176R → W in VHLD. 1
Natural variantiVAR_005767177R → RLRVKPE in VHLD; type I. 1
Natural variantiVAR_005768178L → P in VHLD; type I-II; common mutation. 1 Publication1
Natural variantiVAR_005769178L → Q in VHLD; type II. Corresponds to variant dbSNP:rs5030822Ensembl.1
Natural variantiVAR_005770180I → V in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs377715747Ensembl.1
Natural variantiVAR_005772184L → P in VHLD; type I. 2 Publications1
Natural variantiVAR_005771184L → R in VHLD; type I. 1 Publication1
Natural variantiVAR_005773186E → K in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs367545984Ensembl.1
Natural variantiVAR_005774186Missing in VHLD. 1 Publication1
Natural variantiVAR_005775188L → P in VHLD; type I-II. 1 Publication1
Natural variantiVAR_005776188L → Q in VHLD; type I. 1 Publication1
Natural variantiVAR_005777188L → V in ECYT2, pheochromocytoma and VHLD; type IIA. 2 PublicationsCorresponds to variant dbSNP:rs5030824Ensembl.1
Natural variantiVAR_005778198L → R in ECYT2 and VHLD; type II. 1
Natural variantiVAR_005779200R → W in ECYT2 and VHLD; type I. 4 PublicationsCorresponds to variant dbSNP:rs28940298Ensembl.1
Erythrocytosis, familial, 2 (ECYT2)2 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive disorder characterized by an increase in serum red blood cell mass, hypersensitivity of erythroid progenitors to erythropoietin, increased erythropoietin serum levels, and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events.
See also OMIM:263400
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_034994126D → Y in ECYT2. 1 PublicationCorresponds to variant dbSNP:rs104893831Ensembl.1
Natural variantiVAR_005733130V → L in ECYT2 and VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs104893830Ensembl.1
Natural variantiVAR_005777188L → V in ECYT2, pheochromocytoma and VHLD; type IIA. 2 PublicationsCorresponds to variant dbSNP:rs5030824Ensembl.1
Natural variantiVAR_034999191H → D in ECYT2. 1 PublicationCorresponds to variant dbSNP:rs28940301Ensembl.1
Natural variantiVAR_035000192P → S in ECYT2. 1 PublicationCorresponds to variant dbSNP:rs28940300Ensembl.1
Natural variantiVAR_005778198L → R in ECYT2 and VHLD; type II. 1
Natural variantiVAR_005779200R → W in ECYT2 and VHLD; type I. 4 PublicationsCorresponds to variant dbSNP:rs28940298Ensembl.1
Renal cell carcinoma (RCC)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionRenal cell carcinoma is a heterogeneous group of sporadic or hereditary carcinoma derived from cells of the proximal renal tubular epithelium. It is subclassified into clear cell renal carcinoma (non-papillary carcinoma), papillary renal cell carcinoma, chromophobe renal cell carcinoma, collecting duct carcinoma with medullary carcinoma of the kidney, and unclassified renal cell carcinoma. Clear cell renal cell carcinoma is the most common subtype.
See also OMIM:144700
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_008101155V → M in VHLD; with RCC. Corresponds to variant dbSNP:rs869025659Ensembl.1
Natural variantiVAR_034998163L → P in RCC; with paraneoplastic erythrocytosis; inhibits binding to HIF1AN. 2 PublicationsCorresponds to variant dbSNP:rs28940297Ensembl.1
Natural variantiVAR_008103166V → D in VHLD; with RCC. 1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi98Y → N: No interaction with HIF1A. No HIF1A degradation. 1 Publication1

Keywords - Diseasei

Congenital erythrocytosis, Disease mutation, Tumor suppressor

Organism-specific databases

DisGeNETi7428.
MalaCardsiVHL.
MIMi144700. phenotype.
171300. phenotype.
193300. phenotype.
263400. phenotype.
OpenTargetsiENSG00000134086.
Orphaneti238557. Chuvash erythrocytosis.
892. Von Hippel-Lindau disease.
PharmGKBiPA37307.

Chemistry databases

ChEMBLiCHEMBL3108660.

Polymorphism and mutation databases

BioMutaiVHL.
DMDMi4033778.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000658091 – 213Von Hippel-Lindau disease tumor suppressorAdd BLAST213

Proteomic databases

EPDiP40337.
MaxQBiP40337.
PaxDbiP40337.
PeptideAtlasiP40337.
PRIDEiP40337.

PTM databases

iPTMnetiP40337.
PhosphoSitePlusiP40337.

Expressioni

Tissue specificityi

Expressed in the adult and fetal brain and kidney.

Developmental stagei

At 4-10 weeks pc, strong expression in the developing central nervous system, kidneys, testis and lung. Differentially expressed within renal tubules.1 Publication

Gene expression databases

BgeeiENSG00000134086.
CleanExiHS_VHL.
ExpressionAtlasiP40337. baseline and differential.
GenevisibleiP40337. HS.

Organism-specific databases

HPAiCAB005430.
HPA031631.
HPA031632.

Interactioni

Subunit structurei

Component of the VCB (VHL-Elongin BC-CUL2) complex; this complex acts as a ubiquitin-ligase E3 and directs proteasome-dependent degradation of targeted proteins. Interacts with CUL2; this interaction is dependent on the integrity of the trimeric VBC complex. Interacts (via the beta domain) with HIF1A (via the NTAD domain); this interaction mediates degradation of HIF1A in normoxia and, in hypoxia, prevents ubiquitination and degradation of HIF1A by mediating hypoxia-induced translocation to the nucleus, a process which requires a hypoxia-dependent regulatory signal. Interacts with ADRB2; the interaction, in normoxia, is dependent on hydroxylation of ADRB2 and the subsequent VCB-mediated ubiquitination and degradation of ADRB2. Under hypoxia, hydroxylation, interaction with VHL, ubiquitination and subsequent degradation of ADRB2 are dramatically decreased. Interacts with RNF139, USP33 and JADE1. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, ELOB and CUL2. Isoform 1 and isoform 3 interact with LIMD1 (via LIM zinc-binding 2), AJUBA (via LIM domains) and WTIP (via LIM domains). Interacts with EPAS1. Interacts with CARD9.16 Publications

Binary interactionsi

Show more details

GO - Molecular functioni

  • enzyme binding Source: UniProtKB
  • transcription factor binding Source: UniProtKB
Complete GO annotation...

Protein-protein interaction databases

BioGridi113269. 353 interactors.
DIPiDIP-32585N.
IntActiP40337. 44 interactors.
MINTiMINT-133223.
STRINGi9606.ENSP00000256474.

Chemistry databases

BindingDBiP40337.

Structurei

Secondary structure

1213
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Beta strandi71 – 78Combined sources8
Beta strandi80 – 82Combined sources3
Beta strandi84 – 89Combined sources6
Beta strandi91 – 93Combined sources3
Beta strandi95 – 97Combined sources3
Beta strandi105 – 112Combined sources8
Beta strandi116 – 121Combined sources6
Turni122 – 124Combined sources3
Beta strandi127 – 130Combined sources4
Beta strandi142 – 144Combined sources3
Beta strandi147 – 152Combined sources6
Helixi158 – 169Combined sources12
Helixi172 – 177Combined sources6
Beta strandi178 – 180Combined sources3
Helixi183 – 189Combined sources7
Helixi194 – 206Combined sources13

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1LM8X-ray1.85V54-213[»]
1LQBX-ray2.00C54-213[»]
1VCBX-ray2.70C/F/I/L54-213[»]
3ZRCX-ray2.90C/F/I/L54-213[»]
3ZRFX-ray2.80C/F/I/L54-213[»]
3ZTCX-ray2.65C/F/I/L54-213[»]
3ZTDX-ray2.79C/F/I/L54-213[»]
3ZUNX-ray2.50C/F/I/L54-213[»]
4AJYX-ray1.73V54-213[»]
4AWJX-ray2.50C/F/I/L54-213[»]
4B95X-ray2.80C/F/I/L54-213[»]
4B9KX-ray2.00C/F/I/L54-213[»]
4BKSX-ray2.20C/F/I/L54-213[»]
4BKTX-ray2.35C/F/I/L54-213[»]
4W9CX-ray2.20C/F/I/L54-213[»]
4W9DX-ray2.20C/F/I/L54-213[»]
4W9EX-ray2.60C/F/I/L54-213[»]
4W9FX-ray2.10C/F/I/L54-213[»]
4W9GX-ray2.70C/F/I/L54-213[»]
4W9HX-ray2.10C/F/I/L54-213[»]
4W9IX-ray2.40C/F/I/L54-213[»]
4W9JX-ray2.20C/F/I/L54-213[»]
4W9KX-ray2.10C/F/I/L54-213[»]
4W9LX-ray2.20C/F/I/L54-213[»]
4WQOX-ray3.20A1-213[»]
5LLIX-ray2.40C/F/I/L54-213[»]
5T35X-ray2.70D/H54-213[»]
DisProtiDP00287.
ProteinModelPortaliP40337.
SMRiP40337.
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP40337.

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati14 – 1815
Repeati19 – 2325
Repeati24 – 2835
Repeati29 – 3345
Repeati34 – 3855
Repeati39 – 4365
Repeati44 – 4875
Repeati49 – 5385

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni14 – 538 X 5 AA tandem repeats of G-[PAVG]-E-E-[DAYSLE]Add BLAST40
Regioni100 – 155Involved in binding to CCT complexAdd BLAST56
Regioni157 – 166Interaction with Elongin BC complex10

Domaini

The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x3-C-x3-[AILV].

Sequence similaritiesi

Belongs to the VHL family.Curated

Keywords - Domaini

Repeat

Phylogenomic databases

eggNOGiKOG4710. Eukaryota.
ENOG4111PRU. LUCA.
GeneTreeiENSGT00390000014353.
HOGENOMiHOG000030904.
HOVERGENiHBG044781.
InParanoidiP40337.
KOiK03871.
OMAiYWIDYQG.
OrthoDBiEOG091G0NHA.
PhylomeDBiP40337.
TreeFamiTF318985.

Family and domain databases

CDDicd05468. pVHL. 1 hit.
Gene3Di1.10.750.10. 1 hit.
2.60.40.780. 1 hit.
InterProiView protein in InterPro
IPR002714. VHL.
IPR024048. VHL_alpha_dom.
IPR024053. VHL_beta_dom.
IPR022772. VHL_tumour_suppress_b/a_dom.
PANTHERiPTHR15160:SF10. PTHR15160:SF10. 1 hit.
PfamiView protein in Pfam
PF01847. VHL. 1 hit.
PF17211. VHL_C. 1 hit.
SUPFAMiSSF49468. SSF49468. 1 hit.

Sequences (3)i

Sequence statusi: Complete.

This entry describes 3 isoformsi produced by alternative splicing and alternative initiation. AlignAdd to basket

Isoform 1 (identifier: P40337-1) [UniParc]FASTAAdd to basket
Also known as: VHL30, VHLp24(MPR)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

« Hide

        10         20         30         40         50
MPRRAENWDE AEVGAEEAGV EEYGPEEDGG EESGAEESGP EESGPEELGA 
        60         70         80         90        100
EEEMEAGRPR PVLRSVNSRE PSQVIFCNRS PRVVLPVWLN FDGEPQPYPT 
       110        120        130        140        150
LPPGTGRRIH SYRGHLWLFR DAGTHDGLLV NQTELFVPSL NVDGQPIFAN 
       160        170        180        190        200
ITLPVYTLKE RCLQVVRSLV KPENYRRLDI VRSLYEDLED HPNVQKDLER 
       210 
LTQERIAHQR MGD
Note: Major isoform.
Length:213
Mass (Da):24,153
Last modified:December 15, 1998 - v2
Checksum:iBA5D6765FBC16EA7
GO
Isoform 2 (identifier: P40337-2) [UniParc]FASTAAdd to basket

The sequence of this isoform differs from the canonical sequence as follows:
     114-154: Missing.

Show »
Length:172
Mass (Da):19,654
Checksum:i46E2C22E8C98393D
GO
Isoform 3 (identifier: P40337-3) [UniParc]FASTAAdd to basket
Also known as: VHL19, VHLp18(MEA)

The sequence of this isoform differs from the canonical sequence as follows:
     1-53: Missing.

Note: Produced by alternative initiation at Met-54 of isoform 1.
Show »
Length:160
Mass (Da):18,532
Checksum:i2644C3B8C3A87D64
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_03456225P → L in pheochromocytoma. 3 PublicationsCorresponds to variant dbSNP:rs35460768Ensembl.1
Natural variantiVAR_00567038S → P in VHLD; type II. 1 Publication1
Natural variantiVAR_00567152E → K in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs373068386Ensembl.1
Natural variantiVAR_03498763L → P in pheochromocytoma. 1 PublicationCorresponds to variant dbSNP:rs104893827Ensembl.1
Natural variantiVAR_03498864R → P in pheochromocytoma. 1 PublicationCorresponds to variant dbSNP:rs104893826Ensembl.1
Natural variantiVAR_03498965S → A in pheochromocytoma. 1 PublicationCorresponds to variant dbSNP:rs869025616Ensembl.1
Natural variantiVAR_00567265S → L in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030826Ensembl.1
Natural variantiVAR_00567365S → W in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030826Ensembl.1
Natural variantiVAR_00567466 – 73Missing in VHLD; type I. 8
Natural variantiVAR_00567568S → W in pheochromocytoma and VHLD; type II. 2 Publications1
Natural variantiVAR_00567670E → K in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030802Ensembl.1
Natural variantiVAR_00567774V → G in VHLD; type I-II. 1 PublicationCorresponds to variant dbSNP:rs5030803Ensembl.1
Natural variantiVAR_03499075Missing in VHLD. 1 Publication1
Natural variantiVAR_00567976F → I in VHLD; type I. 1 Publication1
Natural variantiVAR_00568076F → L in VHLD; type I. 1 Publication1
Natural variantiVAR_00568176F → S in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs730882033Ensembl.1
Natural variantiVAR_00567876Missing in VHLD; type I; common mutation. 1 Publication1
Natural variantiVAR_00568278N → H in VHLD; type I. 1 Publication1
Natural variantiVAR_00568378N → S in VHLD; type I; common mutation. 1 PublicationCorresponds to variant dbSNP:rs5030804Ensembl.1
Natural variantiVAR_00568478N → T in VHLD; type I. 1 Publication1
Natural variantiVAR_00568579R → P in VHLD. 1
Natural variantiVAR_00568680S → I in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030805Ensembl.1
Natural variantiVAR_00568880S → N in pheochromocytoma and VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs5030805Ensembl.1
Natural variantiVAR_00568780S → R in VHLD; type I. 2 Publications1
Natural variantiVAR_00568981P → S in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030806Ensembl.1
Natural variantiVAR_00569182 – 84Missing in VHLD. 3
Natural variantiVAR_00569082R → P in VHLD; type I. Corresponds to variant dbSNP:rs794726890Ensembl.1
Natural variantiVAR_00569284V → L in VHLD; type II and type 2C. 2 PublicationsCorresponds to variant dbSNP:rs5030827Ensembl.1
Natural variantiVAR_00569386P → A in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs398123481Ensembl.1
Natural variantiVAR_00809786P → H in VHLD. 1
Natural variantiVAR_00569486P → L in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs730882034Ensembl.1
Natural variantiVAR_00569586P → R in VHLD; type I. 1 Publication1
Natural variantiVAR_00569686P → S in VHLD. 2 PublicationsCorresponds to variant dbSNP:rs398123481Ensembl.1
Natural variantiVAR_00569788W → R in VHLD; type I. 2 Publications1
Natural variantiVAR_00569888W → S in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs119103277Ensembl.1
Natural variantiVAR_00569989L → H in lung cancer. Corresponds to variant dbSNP:rs5030807Ensembl.1
Natural variantiVAR_00570089L → P in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030807Ensembl.1
Natural variantiVAR_00570191F → L in cerebellar hemangioblastoma. 1 Publication1
Natural variantiVAR_00570292 – 97Missing in VHLD; type I. 6
Natural variantiVAR_00570393G → C in pheochromocytoma and VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs5030808Ensembl.1
Natural variantiVAR_00570493G → D in VHLD. 1
Natural variantiVAR_00570593G → S in pheochromocytoma and VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs5030808Ensembl.1
Natural variantiVAR_00570696Q → P in VHLD; type I. 1 Publication1
Natural variantiVAR_00570798Y → H in pheochromocytoma and VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs5030809Ensembl.1
Natural variantiVAR_005708101L → G in VHLD; type I; requires 2 nucleotide substitutions. 1 Publication1
Natural variantiVAR_005709101L → R in VHLD; type I. 1 Publication1
Natural variantiVAR_005710104G → A in cerebellar hemangioblastoma. 1 Publication1
Natural variantiVAR_005711105T → P in VHLD; type I. 1 Publication1
Natural variantiVAR_005712106G → D in lung cancer. 1
Natural variantiVAR_034991107R → G in pheochromocytoma. 1 PublicationCorresponds to variant dbSNP:rs397516440Ensembl.1
Natural variantiVAR_005713107R → P in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs193922609Ensembl.1
Natural variantiVAR_055087110H → Y1 PublicationCorresponds to variant dbSNP:rs17855706Ensembl.1
Natural variantiVAR_005714111S → C in VHLD; type II. 1
Natural variantiVAR_005715111S → N in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs869025631Ensembl.1
Natural variantiVAR_005716111S → R in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs765978945Ensembl.1
Natural variantiVAR_005717112Y → H in VHLD; type IIA. Corresponds to variant dbSNP:rs104893824Ensembl.1
Natural variantiVAR_034992112Y → N in VHLD. 1 PublicationCorresponds to variant dbSNP:rs104893824Ensembl.1
Natural variantiVAR_005718114G → C in VHLD; type II. 1 Publication1
Natural variantiVAR_005719114G → R in VHLD; type I-II. Corresponds to variant dbSNP:rs869025636Ensembl.1
Natural variantiVAR_005720114G → S in VHLD; type II. 1 Publication1
Natural variantiVAR_005723115H → Q in VHLD; type II. 1 Publication1
Natural variantiVAR_008098115H → R in VHLD; type II. Corresponds to variant dbSNP:rs5030812Ensembl.1
Natural variantiVAR_005722115H → Y in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030811Ensembl.1
Natural variantiVAR_005724116L → V in VHLD. 1 Publication1
Natural variantiVAR_005725117W → C in VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs727504215Ensembl.1
Natural variantiVAR_005726118L → P in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs5030830Ensembl.1
Natural variantiVAR_005727118L → R in VHLD. 1 Publication1
Natural variantiVAR_005728119F → L in pheochromocytoma and VHLD; type II. 1 Publication1
Natural variantiVAR_005729119F → S in VHLD; type II. 1 Publication1
Natural variantiVAR_005730121D → G in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs5030832Ensembl.1
Natural variantiVAR_034993122A → I in pheochromocytoma; requires 2 nucleotide substitutions. 1 Publication1
Natural variantiVAR_034994126D → Y in ECYT2. 1 PublicationCorresponds to variant dbSNP:rs104893831Ensembl.1
Natural variantiVAR_005731128L → F in VHLD; type II. 1
Natural variantiVAR_005732129L → LE in VHLD. 1
Natural variantiVAR_005733130V → L in ECYT2 and VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs104893830Ensembl.1
Natural variantiVAR_005734131N → K in VHLD; type I. 1 Publication1
Natural variantiVAR_005735131N → T in VHLD; type I. 1 Publication1
Natural variantiVAR_034995135L → F in hemangioblastoma. 1 PublicationCorresponds to variant dbSNP:rs119103278Ensembl.1
Natural variantiVAR_005737136F → C in pheochromocytoma and VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs5030833Ensembl.1
Natural variantiVAR_005736136F → S in VHLD. 1 PublicationCorresponds to variant dbSNP:rs5030833Ensembl.1
Natural variantiVAR_008099136F → Y in VHLD. 1
Natural variantiVAR_005738143D → E in VHLD; type II. 1 Publication1
Natural variantiVAR_008100145Q → H in VHLD. Corresponds to variant dbSNP:rs771727849Ensembl.1
Natural variantiVAR_034996147I → T in pheochromocytoma. 1 Publication1
Natural variantiVAR_005739148Missing in VHLD; type I. 1
Natural variantiVAR_005740149A → T in VHLD; type II. 1 PublicationCorresponds to variant dbSNP:rs587780077Ensembl.1
Natural variantiVAR_005741154P → L in VHLD; type II. 1
Natural variantiVAR_005742155V → G in VHLD; type II. 1 Publication1
Natural variantiVAR_008101155V → M in VHLD; with RCC. Corresponds to variant dbSNP:rs869025659Ensembl.1
Natural variantiVAR_005743156Y → C in pheochromocytoma and VHLD; type I. 3 PublicationsCorresponds to variant dbSNP:rs397516441Ensembl.1
Natural variantiVAR_005744156Y → D in VHLD; type I. 1 Publication1
Natural variantiVAR_034997156Y → N in pheochromocytoma. 1 Publication1
Natural variantiVAR_005746157T → I in VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs869025660Ensembl.1
Natural variantiVAR_005747157T → TF in VHLD; type I. 1
Natural variantiVAR_005748158L → P in VHLD; type I-II; abolishes release from chaperonin complex and the interaction with Elongin BC complex. 3 PublicationsCorresponds to variant dbSNP:rs121913346Ensembl.1
Natural variantiVAR_005749158L → V in VHLD; type I. 1 Publication1
Natural variantiVAR_005750159K → E in VHLD; type II. 1
Natural variantiVAR_005753161R → G in VHLD; type II. Corresponds to variant dbSNP:rs5030818Ensembl.1
Natural variantiVAR_005752161R → P in pheochromocytoma and VHLD; type I. 2 Publications1
Natural variantiVAR_005751161R → Q in pheochromocytoma and VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs730882035Ensembl.1
Natural variantiVAR_005754162C → F in VHLD; type I; No effect on interaction with HIF1A nor on HIF1A degradation. 4 PublicationsCorresponds to variant dbSNP:rs397516444Ensembl.1
Natural variantiVAR_005755162C → R in VHLD; type I. 1 Publication1
Natural variantiVAR_005756162C → W in VHLD; type I-II. 2 Publications1
Natural variantiVAR_005757162C → Y in VHLD; type I. 1 Publication1
Natural variantiVAR_034998163L → P in RCC; with paraneoplastic erythrocytosis; inhibits binding to HIF1AN. 2 PublicationsCorresponds to variant dbSNP:rs28940297Ensembl.1
Natural variantiVAR_008102164Q → H in VHLD. 1
Natural variantiVAR_005758164Q → R in VHLD; type II. 2 PublicationsCorresponds to variant dbSNP:rs267607170Ensembl.1
Natural variantiVAR_008103166V → D in VHLD; with RCC. 1
Natural variantiVAR_005759166V → F in VHLD; type IIA. 2 PublicationsCorresponds to variant dbSNP:rs104893825Ensembl.1
Natural variantiVAR_005760167R → G in VHLD; type I-II. 1 PublicationCorresponds to variant dbSNP:rs5030820Ensembl.1
Natural variantiVAR_005761167R → Q in pheochromocytoma and VHLD; type II; common mutation. 3 PublicationsCorresponds to variant dbSNP:rs5030821Ensembl.1
Natural variantiVAR_005762167R → W in pheochromocytoma and VHLD; type II; common mutation. 4 PublicationsCorresponds to variant dbSNP:rs5030820Ensembl.1
Natural variantiVAR_005763170V → D in VHLD; type II. 1 Publication1
Natural variantiVAR_005764170V → F in VHLD; type II. 1
Natural variantiVAR_005765170V → G in VHLD; type I. 2 Publications1
Natural variantiVAR_005766175Y → D in VHLD; type I. 1 Publication1
Natural variantiVAR_008104176R → W in VHLD. 1
Natural variantiVAR_005767177R → RLRVKPE in VHLD; type I. 1
Natural variantiVAR_005768178L → P in VHLD; type I-II; common mutation. 1 Publication1
Natural variantiVAR_005769178L → Q in VHLD; type II. Corresponds to variant dbSNP:rs5030822Ensembl.1
Natural variantiVAR_005770180I → V in VHLD; type I. 1 PublicationCorresponds to variant dbSNP:rs377715747Ensembl.1
Natural variantiVAR_005772184L → P in VHLD; type I. 2 Publications1
Natural variantiVAR_005771184L → R in VHLD; type I. 1 Publication1
Natural variantiVAR_005773186E → K in VHLD; type I. 2 PublicationsCorresponds to variant dbSNP:rs367545984Ensembl.1
Natural variantiVAR_005774186Missing in VHLD. 1 Publication1
Natural variantiVAR_005775188L → P in VHLD; type I-II. 1 Publication1
Natural variantiVAR_005776188L → Q in VHLD; type I. 1 Publication1
Natural variantiVAR_005777188L → V in ECYT2, pheochromocytoma and VHLD; type IIA. 2 PublicationsCorresponds to variant dbSNP:rs5030824Ensembl.1
Natural variantiVAR_034999191H → D in ECYT2. 1 PublicationCorresponds to variant dbSNP:rs28940301Ensembl.1
Natural variantiVAR_035000192P → S in ECYT2. 1 PublicationCorresponds to variant dbSNP:rs28940300Ensembl.1
Natural variantiVAR_035001198L → Q in pheochromocytoma. 1 Publication1
Natural variantiVAR_005778198L → R in ECYT2 and VHLD; type II. 1
Natural variantiVAR_005779200R → W in ECYT2 and VHLD; type I. 4 PublicationsCorresponds to variant dbSNP:rs28940298Ensembl.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_0077401 – 53Missing in isoform 3. CuratedAdd BLAST53
Alternative sequenceiVSP_004488114 – 154Missing in isoform 2. 1 PublicationAdd BLAST41

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AF010238 Genomic DNA. Translation: AAB64200.1.
L15409 mRNA. No translation available.
AK315799 mRNA. Translation: BAG38142.1.
AC034193 Genomic DNA. No translation available.
CH471055 Genomic DNA. Translation: EAW64064.1.
BC058831 mRNA. Translation: AAH58831.1.
U54612 Genomic DNA. Translation: AAA98614.1.
X96489 Genomic DNA. Translation: CAA65343.1.
CCDSiCCDS2597.1. [P40337-1]
CCDS2598.1. [P40337-2]
PIRiI38926.
RefSeqiNP_000542.1. NM_000551.3. [P40337-1]
NP_937799.1. NM_198156.2. [P40337-2]
UniGeneiHs.517792.

Genome annotation databases

EnsembliENST00000256474; ENSP00000256474; ENSG00000134086. [P40337-1]
ENST00000345392; ENSP00000344757; ENSG00000134086. [P40337-2]
GeneIDi7428.
KEGGihsa:7428.
UCSCiuc003bvc.4. human. [P40337-1]

Keywords - Coding sequence diversityi

Alternative initiation, Alternative splicing, Polymorphism

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.

Entry informationi

Entry nameiVHL_HUMAN
AccessioniPrimary (citable) accession number: P40337
Secondary accession number(s): B2RE45, Q13599, Q6PDA9
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 1, 1995
Last sequence update: December 15, 1998
Last modified: July 5, 2017
This is version 202 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. SIMILARITY comments
    Index of protein domains and families