P40338 (VHL_MOUSE) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Von Hippel-Lindau disease tumor suppressor

Alternative name(s):
pVHL

Gene names

Name:	Vhl
Synonyms:	Vhlh

Organism

Mus musculus (Mouse) [Reference proteome]

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus › Mus

Protein attributes

Sequence length	181 AA.
Sequence status	Complete.
Protein existence	Evidence at transcript level

General annotation (Comments)

Function	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Seems to act as 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 By similarity.
Pathway	Protein modification; protein ubiquitination.
Subunit structure	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 ubiqitination 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 PHF17 By similarity. Found in a complex composed of LIMD1, VHL, EGLN1/PHD2, TCEB2 AND CUL2. Interacts with LIMD1 (via LIM zinc-binding 2). Interacts with AJUBA (via LIM domains) and WTIP (via LIM domains) By similarity. Interacts with EPAS1 By similarity.
Subcellular location	Cytoplasm By similarity. Membrane; Peripheral membrane protein By similarity. Nucleus By similarity. Note: Colocalizes with ADRB2 at the cell membrane By similarity.
Developmental stage	Expressed throughout fetal nephrogenesis, abdominal and thoracic organogenesis, and nervous system development between day 10.5 and day 16.5. In the developing lung, differential expression within the endodermally derived cuboidal epithelial lining of the terminal and respiratory bronchioles. In the developing eye, high expression in both the inner and outer neuroblastic layers of the retina and lens. Ref.1
Domain	The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV].

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Cytoplasm Membrane Nucleus
Disease	Tumor suppressor
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	angiogenesis Inferred from mutant phenotype PubMed 16537898. Source: MGI blood vessel endothelial cell migration Inferred from mutant phenotype PubMed 16537898. Source: MGI extracellular matrix organization Inferred from mutant phenotype PubMed 16537898. Source: MGI negative regulation of transcription from RNA polymerase II promoter Inferred from electronic annotation. Source: Compara neuron differentiation Inferred from electronic annotation. Source: Compara proteasomal protein catabolic process Inferred from mutant phenotype PubMed 17981124. Source: MGI protein heterooligomerization Inferred from electronic annotation. Source: Compara protein ubiquitination Inferred from electronic annotation. Source: UniProtKB-UniPathway regulation of catecholamine metabolic process Inferred from electronic annotation. Source: Compara response to ethanol Inferred from electronic annotation. Source: Compara response to hypoxia Inferred from electronic annotation. Source: Compara
Cellular_component	VCB complex Inferred from electronic annotation. Source: Compara cytosol Inferred from electronic annotation. Source: Compara membrane Inferred from electronic annotation. Source: UniProtKB-SubCell mitochondrion Inferred from electronic annotation. Source: Compara nucleus Inferred from electronic annotation. Source: UniProtKB-SubCell
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 181	181	Von Hippel-Lindau disease tumor suppressor		PRO_0000065810
Regions
	Region	123 – 132	10	Interaction with Elongin BC complex By similarity

Sequences

	Sequence		Length	Mass (Da)
	P40338 [UniParc]. Last modified February 1, 1995. Version 1. Checksum: AE8B2E8DDD3EE987	FASTA	181	20,770
	10 20 30 40 50 60 MPRKAASPEE AAGEPGPEEM EAGRPRPVLR SVNSREPSQV IFCNRSPRVV LPLWLNFDGE 70 80 90 100 110 120 PQPYPILPPG TGRRIHSYRG HLWLFRDAGT HDGLLVNQTE LFVPSLNVDG QPIFANITLP 130 140 150 160 170 180 VYTLKERCLQ VVRSLVKPEN YRRLDIVRSL YEDLEDYPSV RKDIQRLSQE HLESQHLEEE P

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Expression of the Von Hippel-Lindau tumor suppressor gene, VHL, in human fetal kidney and during mouse embryogenesis." Kessler P.M., Vasavada S.P., Rackley R.R., Stackhouse T., Duh F.-M., Latif F., Lerman M.I., Zbar B., Williams B.R. Mol. Med. 1:457-466(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], DEVELOPMENTAL STAGE. Strain: ICR. Tissue: Brain.
[2]	"Cloning and characterization of a mouse gene with homology to the human von Hippel-Lindau disease tumor suppressor gene: implications for the potential organization of the human von Hippel-Lindau disease gene." Gao J., Naglich J.G., Laidlaw J., Whaley J.M., Seizinger B.R., Kley N. Cancer Res. 55:743-747(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Human DNA blueprints protecting the VHL promoter and CpG island from methylation are functional in the mouse." Kuzmin I., Geil L., Schmidt L., Duh F.-M., Feigenbaum L., Nickerson M.L., Ma W., Stanbridge E.J., Zbar B., Lerman M.I. Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE. Strain: 129/SvJ.
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Strain: C57BL/6.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	U12570 mRNA. Translation: AAA20662.1. S76748 mRNA. Translation: AAB33363.1. AF513984 Genomic DNA. Translation: AAM53645.1. BC052417 mRNA. Translation: AAH52417.2.
IPI	IPI00109233.
RefSeq	NP_033533.1. NM_009507.3.
UniGene	Mm.29407.
3D structure databases
ProteinModelPortal	P40338.
SMR	P40338. Positions 28-170.
ModBase	Search...
Protein-protein interaction databases
IntAct	P40338. 4 interactions.
STRING	10090.ENSMUSP00000039418.
PTM databases
PhosphoSite	P40338.
Proteomic databases
PaxDb	P40338.
PRIDE	P40338.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENSMUST00000035673; ENSMUSP00000039418; ENSMUSG00000033933.
GeneID	22346.
KEGG	mmu:22346.
Organism-specific databases
CTD	7428.
MGI	MGI:103223. Vhl.
Phylogenomic databases
eggNOG	NOG327868.
HOGENOM	HOG000030904.
HOVERGEN	HBG044781.
InParanoid	P40338.
KO	K03871.
OMA	NTREPSQ.
OrthoDB	EOG4J119K.
Enzyme and pathway databases
UniPathway	UPA00143.
Gene expression databases
ArrayExpress	P40338.
Bgee	P40338.
Genevestigator	P40338.
GermOnline	ENSMUSG00000033933. Mus musculus.
Family and domain databases
Gene3D	1.10.750.10. 1 hit. 2.60.40.780. 1 hit.
InterPro	IPR002714. Tumour_suppress_VHL-disease. IPR024048. VHL_alpha_dom. IPR024053. VHL_beta_dom. IPR022772. VHL_tumour_suppress_b/a_dom. [Graphical view]
PANTHER	PTHR15160. PTHR15160. 1 hit.
Pfam	PF01847. VHL. 1 hit. [Graphical view]
SUPFAM	SSF49468. SSF49468. 1 hit.
ProtoNet	Search...
Other
NextBio	302621.
SOURCE	Search...

Entry information

Entry name

VHL_MOUSE

Accession

Primary (citable) accession number: P40338

Entry history

Integrated into UniProtKB/Swiss-Prot:	February 1, 1995
Last sequence update:	February 1, 1995
Last modified:	April 3, 2013
This is version 104 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program