Protein:VHL |
Protein Summary |
 Gene summary |
| Gene name: VHL | ASpdb.0 ID: 7428 | Gene | Gene symbol | VHL | Gene ID | 7428 |
| Gene name | von Hippel-Lindau tumor suppressor |
| Synonyms | HRCA1|RCA1|VHL1|pVHL |
| Cytomap | 3p25.3 |
| Type of gene | protein-coding |
| Description | von Hippel-Lindau disease tumor suppressorelongin binding proteinprotein G7von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase |
| Modification date | 20240411 |
| UniProtAcc | P40337 |
| Gene ontology of this gene with evidence of Inferred from Direct Assay (IDA) from Entrez |
| Partner | Gene | GO ID | GO term | PubMed ID |
| Gene | VHL | GO:0000122 | negative regulation of transcription by RNA polymerase II | 11641274 |
| Gene | VHL | GO:0003711 | transcription elongation factor activity | 7660122 |
| Gene | VHL | GO:0005654 | nucleoplasm | - |
| Gene | VHL | GO:0005783 | endoplasmic reticulum | 34290272 |
| Gene | VHL | GO:0008285 | negative regulation of cell population proliferation | 23338840 |
| Gene | VHL | GO:0010468 | regulation of gene expression | 17973242|23338840 |
| Gene | VHL | GO:0010507 | negative regulation of autophagy | 30902965 |
| Gene | VHL | GO:0016567 | protein ubiquitination | 24899725 |
| Gene | VHL | GO:0034244 | negative regulation of transcription elongation by RNA polymerase II | 7660122 |
| Gene | VHL | GO:0043161 | proteasome-mediated ubiquitin-dependent protein catabolic process | 34290272 |
| Gene | VHL | GO:1904262 | negative regulation of TORC1 signaling | 34290272 |
| Gene | VHL | GO:1990000 | amyloid fibril formation | 34431623 |
| Gene | VHL | GO:1990756 | ubiquitin-like ligase-substrate adaptor activity | 24899725|34290272 |
AS Summary |
| Information of the canonical protein with experimentally identified structure from PDB (2023). |
| UniProt Acc | File name | PDB ID | Method | Resolution | Chain | Start | End |
| P40337-1 | P40337-1_6r7f_V.pdb | 6R7F | EM | 8.2 | V | 54 | 213 |
| ASpdb's canonical and alternatively spliced isoform information. |
| accession_id | gene_name | canonical_id | alternative_id | canonical_length | alternative_length | canonical_start | canonical_end | type | originalSEQ | variationSEQ | alternative_start | alternative_end |
| P40337 | VHL | P40337-1 | P40337-2 | 213 | 172 | 114 | 154 | Deletion | none | none | 113 | 113 |
| P40337 | VHL | P40337-1 | P40337-3 | 213 | 160 | 1 | 53 | Deletion | none | none | 0 | 0 |
| Multiple sequence alignment of our canonical and alternatively spliced VHL |
| Matched gene isoform IDs with Ensembl and RefSeq of our canonical and alternative spliced genes of VHL |
| UniProt-id | ENSG | ENST | ENSP |
| P40337-1 | ENSG00000134086.9 | ENST00000256474.3 | ENSP00000256474.3 |
| P40337-2 | ENSG00000134086.9 | ENST00000345392.2 | ENSP00000344757.2 |
| UniProt-id | NM ID | NP ID |
| P40337-1 | NM_000551.3 | NP_000542.1 |
| P40337-2 | NM_198156.2 | NP_937799.1 |
| Amino acid sequences of our canonical and alternatively spliced VHL |
| accession_id | Protein sequence |
| P40337-1 | MPRRAENWDEAEVGAEEAGVEEYGPEEDGGEESGAEESGPEESGPEELGAEEEMEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLN FDGEPQPYPTLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVDGQPIFANITLPVYTLKERCLQVVRSLVKPENYRRLDI |
| P40337-2 | MPRRAENWDEAEVGAEEAGVEEYGPEEDGGEESGAEESGPEESGPEELGAEEEMEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLN |
| P40337-3 | MEAGRPRPVLRSVNSREPSQVIFCNRSPRVVLPVWLNFDGEPQPYPTLPPGTGRRIHSYRGHLWLFRDAGTHDGLLVNQTELFVPSLNVD |
Protein Functional Features |
| Main function of this protein. (from UniProt) |
| VHL (go to UniProt):P40337 |
| Retention analysis result of protein across 39 protein features of UniProt such as six molecule processing features, 13 region features, four site features, six amino acid modification features, two natural variation features, five experimental info features, and 3 secondary structure features. Here, because of limited space for viewing, we only show the protein feature retention information belong to the 13 regional features. All retention annotation result can be downloaded at * Minus value of BPloci means that the break pointn is located before the CDS. |
| - Retained protein feature among the 13 regional features. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| P40337 | Repeat | 14 | 18 | Note=1 | Type=Deletion;Start=1;End=53 |
| P40337 | Repeat | 19 | 23 | Note=2 | Type=Deletion;Start=1;End=53 |
| P40337 | Repeat | 24 | 28 | Note=3 | Type=Deletion;Start=1;End=53 |
| P40337 | Repeat | 29 | 33 | Note=4 | Type=Deletion;Start=1;End=53 |
| P40337 | Repeat | 34 | 38 | Note=5 | Type=Deletion;Start=1;End=53 |
| P40337 | Repeat | 39 | 43 | Note=6 | Type=Deletion;Start=1;End=53 |
| P40337 | Repeat | 44 | 48 | Note=7 | Type=Deletion;Start=1;End=53 |
| P40337 | Repeat | 49 | 53 | Note=8 | Type=Deletion;Start=1;End=53 |
| P40337 | Region | 1 | 65 | Note=Disordered;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=1;End=53 |
| P40337 | Region | 14 | 53 | Note=8 X 5 AA tandem repeats of G-[PAVG]-E-E-[DAYSLE] | Type=Deletion;Start=1;End=53 |
| P40337 | Region | 100 | 155 | Note=Involved in binding to CCT complex | Type=Deletion;Start=114;End=154 |
| P40337 | Compositional bias | 12 | 50 | Note=Acidic residues;Ontology_term=ECO:0000256;evidence=ECO:0000256|SAM:MobiDB-lite | Type=Deletion;Start=1;End=53 |
Gene Isoform Structures and Expression Levels for VHL |
| Gene structures of our canonical and alternative spliced genes of VHL * Click on the image to open the UCSC genome browser with custom track showing this image in a new window. |
| Expression levels of gene isoforms across GTEx. |
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| Expression levels of gene isoforms across TCGA. |
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Protein Structures |
| PDB and CIF files of the predicted protein structures * Here we show the 3D structure of the proteins using Mol*. AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. Model confidence is shown from the pLDDT values per residue. pLDDT corresponds to the model’s prediction of its score on the local Distance Difference Test. It is a measure of local accuracy (from AlphfaFold website). To color code individual residues, we transformed individual PDB files into CIF format. |
| 3D view using mol* of P40337-1 |
| 3D view using mol* of P40337-2 |
| 3D view using mol* of P40337-3 |
pLDDT Score Distribution |
| pLDDT score distribution of the predicted protein structures from AlphaFold2 * AlphaFold produces a per-residue confidence score (pLDDT) between 0 and 100. |
| pLDDT distribution across the protein length of P40337-1 |
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| pLDDT distribution across the protein length of P40337-2 |
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| pLDDT distribution across the protein length of P40337-3 |
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Ramachandran Plot of Protein Structures |
| Ramachandran plot of the torsional angles - phi (φ)and psi (ψ) - of the residues (amino acids) contained in this protein peptide. |
| Ramachandran plot of P40337-1 |
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| Ramachandran plot of P40337-2 |
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| Ramachandran plot of P40337-3 |
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Potential Active Site Information |
| The potential binding sites of these proteins were identified using SiteMap, a module of the Schrodinger suite. |
| UniProt-id | Site score | Size | D score | Volume | Exposure | Enclosure | Contact | Phobic | Philic | Balance | Don/Acc | Residues |
| P40337-1 | 0.946 | 128 | 0.917 | 387.59 | 0.65 | 0.617 | 0.88 | 0.327 | 1.206 | 0.271 | 0.715 | 48,49,50,51,52,53,54,55,56,57,58,60,61,62,63,64,65 ,66,67,69,89,91,92,93,114,116,135,137,195,198,199, 202,205 |
| P40337-2 | 0.809 | 43 | 0.826 | 144.746 | 0.711 | 0.65 | 0.759 | 0.957 | 0.553 | 1.73 | 1.134 | 74,76,85,86,87,88,98,99,101,107,108,109
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| P40337-3 | 0.845 | 65 | 0.816 | 279.888 | 0.699 | 0.679 | 0.77 | 0.149 | 1.073 | 0.139 | 0.662 | 67,71,72,73,74,101,103,107,110,111,114,134,137,138 ,139,140,143,144,147 |
Protein Structure and Feature Comparision |
| Protein Structure Comparision Using Template Modeling Scores (TM-score). |
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| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Canonical validated structure (PDB)(green) |
| 3D view using mol* of P40337-1_P40337-1_6r7f_V.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical validated structure (PDB)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P40337-1_6r7f_V_P40337-2.pdb |
| 3D view using mol* of P40337-1_6r7f_V_P40337-3.pdb |
| Protein Structure Comparision Visualization with mol*. between Canonical predicted structure (AF2)(orange) vs Alternative predicted structure (AF2)(green) |
| 3D view using mol* of P40337-1_P40337-2.pdb |
| 3D view using mol* of P40337-1_P40337-3.pdb |
| Protein Feature Comparison of the protein sequendary structures among the protiens. |
| ./stats/secondary_structure/figure/P40337-1_vs_P40337-2.png |
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| ./stats/secondary_structure/figure/P40337-1_vs_P40337-3.png |
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| Protein Feature Comparison of the relative accessible surface area (ASA) among the protiens. |
| ./stats/relative_asa/P40337-1_vs_P40337-2.png |
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| ./stats/relative_asa/P40337-1_vs_P40337-3.png |
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Protein-Protein Interaction |
| Interactors from UniProt. |
| Accession_id | Subsection | Start | End | Funcitonal feature | Splicing information |
| Interactors from STRING. |
| Gene name | Interactors |
Related Drugs to VHL |
| Drugs targeting this gene/protein. (DrugBank) |
| UniProt accession | Gene name | DrugBank ID | Drug name | Drug group | Actions |
Related Diseases to VHL |
| Previous studies relating to the alternative splicing of VHL and disease information from the MeSH term (PubMed) |
| Gene | PMID | Title | Abstract | MeSH ID | MeSH term |
| VHL | 19056930 | von Hippel-Lindau tumor suppressor gene-dependent mRNA stabilization of the survival factor parathyroid hormone-related protein in human renal cell carcinoma by the RNA-binding protein HuR. | We have shown that parathyroid hormone-related protein (PTHrP) is a survival factor for human renal cell carcinoma (RCC) and that its expression is negatively regulated by the von Hippel-Lindau (VHL) tumor suppressor gene at the level of messenger RNA (mRNA) stability, as observed for tumor growth factors (TGFs). Our goals were to analyze the alternative splicing of PTHrP mRNA in human RCC and from these results to identify VHL/hypoxia-induced factor (HIF) system-regulated mRNA-binding proteins involved in PTHrP mRNA stability. We used: (i) a panel of human RCC cells expressing or not VHL; (ii) VHL-deficient 786-0 cells transfected with active or inactive VHL and (iii) human RCC samples and corresponding normal tissues. By quantitative real-time reverse transcription-polymerase chain reaction analysis, the 141 PTHrP mRNA isoform was found to be predominant in all cells and tumors (80%). In cells transfected with VHL, the expressions of all isoforms were decreased by 50%. Eight proteins with molecular weights ranging from 20 to 75 kDa were found to bind to biotinylated transcripts spanning the 141 PTHrP mRNA AU-rich 3'-untranslated region whose abundancy was dependent on VHL expression. The protein having an apparent molecular weight of 30 kDa was identified by western blot as HuR, a RNA-binding protein with stabilizing functions on various mRNA coding for proteins important in malignant transformation including vascular endothelial growth factor and TGF-beta. PTHrP expression studies confirmed the involvement of HuR in PTHrP upregulation in this disease. Common mRNA-binding proteins regulated by the VHL/HIF system may constitute new therapeutic opportunities against human RCC that remains refractory to therapies. | D002292 | Carcinoma, Renal Cell |
| VHL | 19056930 | von Hippel-Lindau tumor suppressor gene-dependent mRNA stabilization of the survival factor parathyroid hormone-related protein in human renal cell carcinoma by the RNA-binding protein HuR. | We have shown that parathyroid hormone-related protein (PTHrP) is a survival factor for human renal cell carcinoma (RCC) and that its expression is negatively regulated by the von Hippel-Lindau (VHL) tumor suppressor gene at the level of messenger RNA (mRNA) stability, as observed for tumor growth factors (TGFs). Our goals were to analyze the alternative splicing of PTHrP mRNA in human RCC and from these results to identify VHL/hypoxia-induced factor (HIF) system-regulated mRNA-binding proteins involved in PTHrP mRNA stability. We used: (i) a panel of human RCC cells expressing or not VHL; (ii) VHL-deficient 786-0 cells transfected with active or inactive VHL and (iii) human RCC samples and corresponding normal tissues. By quantitative real-time reverse transcription-polymerase chain reaction analysis, the 141 PTHrP mRNA isoform was found to be predominant in all cells and tumors (80%). In cells transfected with VHL, the expressions of all isoforms were decreased by 50%. Eight proteins with molecular weights ranging from 20 to 75 kDa were found to bind to biotinylated transcripts spanning the 141 PTHrP mRNA AU-rich 3'-untranslated region whose abundancy was dependent on VHL expression. The protein having an apparent molecular weight of 30 kDa was identified by western blot as HuR, a RNA-binding protein with stabilizing functions on various mRNA coding for proteins important in malignant transformation including vascular endothelial growth factor and TGF-beta. PTHrP expression studies confirmed the involvement of HuR in PTHrP upregulation in this disease. Common mRNA-binding proteins regulated by the VHL/HIF system may constitute new therapeutic opportunities against human RCC that remains refractory to therapies. | D007680 | Kidney Neoplasms |
Clinically important variants in VHL |
| (ClinVar, 04/20/2024) |
| accession_id | uniprot_id | gene_name | Type | Variant | Clinical_significance |
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