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UniProtKB/Swiss-Prot P40337 (VHL_HUMAN)
Last modified
November 25, 2008.
Version 102.
History...
Clusters with 100%,
90%,
50% identity |
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Names and origin
| Protein names | Recommended name: Von Hippel-Lindau disease tumor suppressor Alternative name(s): pVHL Protein G7 | ||
| Gene names |
| ||
| Organism | Homo sapiens (Human) | ||
| Taxonomic identifier | 9606 [NCBI] | ||
| Taxonomic lineage | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Protein attributes
| Sequence length | 213 AA. |
| Sequence status | Complete. |
| Sequence processing | The displayed sequence is not processed. |
| Protein existence | Evidence at protein 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. |
| Pathway | |
| Subunit structure | Component of the VCB (VHL-Elongin BC-CUL2) complex; this complex acts as a ubiquitin-ligase E3 and directs proteosome-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 RNF139 and UBP33. Interacts with PHF17. |
| Subcellular location | Isoform 1: Cytoplasm. Membrane; Peripheral membrane protein. Nucleus. Note= Found predominantly in the cytoplasm and with less amounts nuclear or membrane-associated. Isoform 3: Cytoplasm. Nucleus. Note= Equally distributed between the nucleus and the cytoplasm but not membrane-associated. |
| Tissue specificity | Expressed in the adult and fetal brain and kidney. |
| Domain | The Elongin BC complex binding domain is also known as BC-box with the consensus [APST]-L-x(3)-C-x(3)-[AILV]. |
| Involvement in disease | Defects in VHL are a cause of pheochromocytoma [MIM:171300]. The pheochromocytomas are catecholamine-producing, chromaffin tumors that arise in the adrenal medulla in 90% of cases. In the remaining 10% of cases, they develop in extra-adrenal sympathetic ganglia and may be referred to as "paraganglioma." Pheochromocytoma usually presents with hypertension. Approximately 10% of pheochromocytoma is hereditary. The genetic basis for most cases of non-syndromic familial pheochromocytoma is unknown. Defects in VHL are the cause of von Hippel-Lindau disease (VHLD) [MIM:193300]. VHLD is a dominantly inherited familial cancer syndrome characterized by the development of retinal angiomatosis, cerebellar and spinal hemangioblastoma, renal cell carcinoma (RCC), phaeochromocytoma 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). VHL type 2C refers to patients with isolated pheochromocytoma without hemangioblastoma or renal cell carcinoma. The estimated incidence is 3/100000 births per year and penetrance is 97% by age 60 years. Defects in VHL are the cause of erythrocytosis familial type 2 (ECYT2) [MIM:263400]; also called VHL-dependent polycythemia or Chuvash type polycythemia. ECYT2 is an 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. Defects in VHL are a cause of renal cell carcinoma type 1 (RCC1) [MIM:144700]; also called hypernephroma or adenocarcinoma of kidney. Familial renal cell carcinoma syndromes form a group of diseases characterized by a predisposition to development of renal cell carcinomas (RCCs) with various histological subtypes. |
Ontologies
Binary interactions
Alternative products
| This entry describes 3 isoforms produced by alternative splicing. [Align] [Select] | ||||||
| Isoform 1 (identifier: P40337-1) 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. | ||||||
| Notes: Found predominantly in the cytoplasm and with less amounts nuclear or membrane-associated. Major isoform. | ||||||
| Isoform 2 (identifier: P40337-2) The sequence of this isoform differs from the canonical sequence as follows: 115-154: Missing. | ||||||
| Isoform 3 (identifier: P40337-3) Also known as: VHL19; VHLp18(MEA); The sequence of this isoform differs from the canonical sequence as follows: 1-53: Missing. | ||||||
| Notes: Equally distributed between the nucleus and the cytoplasm but not membrane-associated. |
Sequence annotation (Features)
| Feature key | Position(s) | Length | Description | Graphical view | Feature identifier | ||||
Molecule processing | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| Chain | 1 – 213 | 213 | Von Hippel-Lindau disease tumor suppressor | PRO_0000065809 | |||||
Regions | |||||||||
| Repeat | 14 – 18 | 5 | 1 | ||||||
| Repeat | 19 – 23 | 5 | 2 | ||||||
| Repeat | 24 – 28 | 5 | 3 | ||||||
| Repeat | 29 – 33 | 5 | 4 | ||||||
| Repeat | 34 – 38 | 5 | 5 | ||||||
| Repeat | 39 – 43 | 5 | 6 | ||||||
| Repeat | 44 – 48 | 5 | 7 | ||||||
| Repeat | 49 – 53 | 5 | 8 | ||||||
| Region | 14 – 53 | 40 | 8 X 5 AA tandem repeats of G-[PAVG]-E-E-[DAYSLE] | ||||||
| Region | 100 – 155 | 56 | Involved in binding to CCT complex | ||||||
| Region | 157 – 166 | 10 | Interaction with Elongin BC complex | ||||||
Natural variations | |||||||||
| Alternative sequence | 1 – 53 | 53 | Missing in isoform 3. | VSP_007740 | |||||
| Alternative sequence | 115 – 154 | 40 | Missing in isoform 2. | VSP_004488 | |||||
| Natural variant | 25 | 1 | P → L in pheochromocytoma. dbSNP rs35460768. | VAR_034562 | |||||
| Natural variant | 38 | 1 | S → P in VHLD; type II. | VAR_005670 | |||||
| Natural variant | 52 | 1 | E → K in VHLD; type I. | VAR_005671 | |||||
| Natural variant | 63 | 1 | L → P in pheochromocytoma. | VAR_034987 | |||||
| Natural variant | 64 | 1 | R → P in pheochromocytoma. | VAR_034988 | |||||
| Natural variant | 65 | 1 | S → A in pheochromocytoma. | VAR_034989 | |||||
| Natural variant | 65 | 1 | S → L in VHLD; type I. | VAR_005672 | |||||
| Natural variant | 65 | 1 | S → W in VHLD; type I. | VAR_005673 | |||||
| Natural variant | 66 – 73 | 8 | Missing in VHLD; type I. | VAR_005674 | |||||
| Natural variant | 68 | 1 | S → W in pheochromocytoma and VHLD; type II. | VAR_005675 | |||||
| Natural variant | 70 | 1 | E → K in VHLD; type I. | VAR_005676 | |||||
| Natural variant | 74 | 1 | V → G in VHLD; type I-II. dbSNP rs5030803. | VAR_005677 | |||||
| Natural variant | 75 | 1 | Missing in VHLD. | VAR_034990 | |||||
| Natural variant | 76 | 1 | F → I in VHLD; type I. | VAR_005679 | |||||
| Natural variant | 76 | 1 | F → L in VHLD; type I. | VAR_005680 | |||||
| Natural variant | 76 | 1 | F → S in VHLD; type I. | VAR_005681 | |||||
| Natural variant | 76 | 1 | Missing in VHLD; type I; common mutation. | VAR_005678 | |||||
| Natural variant | 78 | 1 | N → H in VHLD; type I. | VAR_005682 | |||||
| Natural variant | 78 | 1 | N → S in VHLD; type I; common mutation. dbSNP rs5030804. | VAR_005683 | |||||
| Natural variant | 78 | 1 | N → T in VHLD; type I. | VAR_005684 | |||||
| Natural variant | 79 | 1 | R → P in VHLD. | VAR_005685 | |||||
| Natural variant | 80 | 1 | S → I in VHLD; type I. | VAR_005686 | |||||
| Natural variant | 80 | 1 | S → N in pheochromocytoma and VHLD; type I. dbSNP rs5030805. | VAR_005688 | |||||
| Natural variant | 80 | 1 | S → R in VHLD; type I. | VAR_005687 | |||||
| Natural variant | 81 | 1 | P → S in VHLD; type I. dbSNP rs5030806. | VAR_005689 | |||||
| Natural variant | 82 – 84 | 3 | Missing in VHLD. | VAR_005691 | |||||
| Natural variant | 82 | 1 | R → P in VHLD; type I. | VAR_005690 | |||||
| Natural variant | 84 | 1 | V → L in VHLD; type II and type 2C. dbSNP rs5030827. | VAR_005692 | |||||
| Natural variant | 86 | 1 | P → A in VHLD; type I. | VAR_005693 | |||||
| Natural variant | 86 | 1 | P → H in VHLD. | VAR_008097 | |||||
| Natural variant | 86 | 1 | P → L in VHLD; type I. | VAR_005694 | |||||
| Natural variant | 86 | 1 | P → R in VHLD; type I. | VAR_005695 | |||||
| Natural variant | 86 | 1 | P → S in VHLD. | VAR_005696 | |||||
| Natural variant | 88 | 1 | W → R in VHLD; type I. | VAR_005697 | |||||
| Natural variant | 88 | 1 | W → S in VHLD; type I. | VAR_005698 | |||||
| Natural variant | 89 | 1 | L → H in lung cancer. | VAR_005699 | |||||
| Natural variant | 89 | 1 | L → P in VHLD; type I. dbSNP rs5030807. | VAR_005700 | |||||
| Natural variant | 91 | 1 | F → L in cerebellar hemangioblastoma. | VAR_005701 | |||||
| Natural variant | 92 – 97 | 6 | Missing in VHLD; type I. | VAR_005702 | |||||
| Natural variant | 93 | 1 | G → C in pheochromocytoma and VHLD; type II. dbSNP rs5030808. | VAR_005703 | |||||
| Natural variant | 93 | 1 | G → D in VHLD. | VAR_005704 | |||||
| Natural variant | 93 | 1 | G → S in pheochromocytoma and VHLD; type II. dbSNP rs5030808. | VAR_005705 | |||||
| Natural variant | 96 | 1 | Q → P in VHLD; type I. | VAR_005706 | |||||
| Natural variant | 98 | 1 | Y → H in pheochromocytoma and VHLD; type II. dbSNP rs5030809. | VAR_005707 | |||||
| Natural variant | 101 | 1 | L → G in VHLD; type I; requires 2 nucleotide substitutions. | VAR_005708 | |||||
| Natural variant | 101 | 1 | L → R in VHLD; type I. | VAR_005709 | |||||
| Natural variant | 104 | 1 | G → A in cerebellar hemangioblastoma. | VAR_005710 | |||||
| Natural variant | 105 | 1 | T → P in VHLD; type I. | VAR_005711 | |||||
| Natural variant | 106 | 1 | G → D in lung cancer. | VAR_005712 | |||||
| Natural variant | 107 | 1 | R → G in pheochromocytoma. | VAR_034991 | |||||
| Natural variant | 107 | 1 | R → P in VHLD; type I. | VAR_005713 | |||||
| Natural variant | 111 | 1 | S → C in VHLD; type II. | VAR_005714 | |||||
| Natural variant | 111 | 1 | S → N in VHLD; type I. | VAR_005715 | |||||
| Natural variant | 111 | 1 | S → R in VHLD; type I. | VAR_005716 | |||||
| Natural variant | 112 | 1 | Y → H in VHLD; type IIA. | VAR_005717 | |||||
| Natural variant | 112 | 1 | Y → N in VHLD. | VAR_034992 | |||||
| Natural variant | 114 | 1 | G → C in VHLD; type II. | VAR_005718 | |||||
| Natural variant | 114 | 1 | G → R in VHLD; type I-II. | VAR_005719 | |||||