Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family.
Activity of the hypoxia-inducible factor (HIF) complex is controlled by oxygen-dependent hydroxylation of prolyl and asparaginyl residues. Hydroxylation of specific prolyl residues by 2-oxoglutarate (2-OG)-dependent oxygenases mediates ubiquitinylation and proteasomal destruction of HIF-alpha. Hydro...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
2002
|
| _version_ | 1826276182753017856 |
|---|---|
| author | Hewitson, K McNeill, L Riordan, M Tian, Y Bullock, A Welford, R Elkins, J Oldham, N Bhattacharya, S Gleadle, J Ratcliffe, P Pugh, C Schofield, C |
| author_facet | Hewitson, K McNeill, L Riordan, M Tian, Y Bullock, A Welford, R Elkins, J Oldham, N Bhattacharya, S Gleadle, J Ratcliffe, P Pugh, C Schofield, C |
| author_sort | Hewitson, K |
| collection | OXFORD |
| description | Activity of the hypoxia-inducible factor (HIF) complex is controlled by oxygen-dependent hydroxylation of prolyl and asparaginyl residues. Hydroxylation of specific prolyl residues by 2-oxoglutarate (2-OG)-dependent oxygenases mediates ubiquitinylation and proteasomal destruction of HIF-alpha. Hydroxylation of an asparagine residue in the C-terminal transactivation domain (CAD) of HIF-alpha abrogates interaction with p300, preventing transcriptional activation. Yeast two-hybrid assays recently identified factor inhibiting HIF (FIH) as a protein that associates with the CAD region of HIF-alpha. Since FIH contains certain motifs present in iron- and 2-OG-dependent oxygenases we investigated whether FIH was the HIF asparaginyl hydroxylase. Assays using recombinant FIH and HIF-alpha fragments revealed that FIH is the enzyme that hydroxylates the CAD asparagine residue, that the activity is directly inhibited by cobalt(II) and limited by hypoxia, and that the oxygen in the alcohol of the hydroxyasparagine residue is directly derived from dioxygen. Sequence analyses involving FIH link the 2-OG oxygenases with members of the cupin superfamily, including Zn(II)-utilizing phosphomannose isomerase, revealing structural and evolutionary links between these metal-binding proteins that share common motifs. |
| first_indexed | 2024-03-06T23:10:10Z |
| format | Journal article |
| id | oxford-uuid:652ea231-c694-4457-ac8b-c9742164fc20 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:10:10Z |
| publishDate | 2002 |
| record_format | dspace |
| spelling | oxford-uuid:652ea231-c694-4457-ac8b-c9742164fc202022-03-26T18:23:52ZHypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:652ea231-c694-4457-ac8b-c9742164fc20EnglishSymplectic Elements at Oxford2002Hewitson, KMcNeill, LRiordan, MTian, YBullock, AWelford, RElkins, JOldham, NBhattacharya, SGleadle, JRatcliffe, PPugh, CSchofield, CActivity of the hypoxia-inducible factor (HIF) complex is controlled by oxygen-dependent hydroxylation of prolyl and asparaginyl residues. Hydroxylation of specific prolyl residues by 2-oxoglutarate (2-OG)-dependent oxygenases mediates ubiquitinylation and proteasomal destruction of HIF-alpha. Hydroxylation of an asparagine residue in the C-terminal transactivation domain (CAD) of HIF-alpha abrogates interaction with p300, preventing transcriptional activation. Yeast two-hybrid assays recently identified factor inhibiting HIF (FIH) as a protein that associates with the CAD region of HIF-alpha. Since FIH contains certain motifs present in iron- and 2-OG-dependent oxygenases we investigated whether FIH was the HIF asparaginyl hydroxylase. Assays using recombinant FIH and HIF-alpha fragments revealed that FIH is the enzyme that hydroxylates the CAD asparagine residue, that the activity is directly inhibited by cobalt(II) and limited by hypoxia, and that the oxygen in the alcohol of the hydroxyasparagine residue is directly derived from dioxygen. Sequence analyses involving FIH link the 2-OG oxygenases with members of the cupin superfamily, including Zn(II)-utilizing phosphomannose isomerase, revealing structural and evolutionary links between these metal-binding proteins that share common motifs. |
| spellingShingle | Hewitson, K McNeill, L Riordan, M Tian, Y Bullock, A Welford, R Elkins, J Oldham, N Bhattacharya, S Gleadle, J Ratcliffe, P Pugh, C Schofield, C Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. |
| title | Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. |
| title_full | Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. |
| title_fullStr | Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. |
| title_full_unstemmed | Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. |
| title_short | Hypoxia-inducible factor (HIF) asparagine hydroxylase is identical to factor inhibiting HIF (FIH) and is related to the cupin structural family. |
| title_sort | hypoxia inducible factor hif asparagine hydroxylase is identical to factor inhibiting hif fih and is related to the cupin structural family |
| work_keys_str_mv | AT hewitsonk hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT mcneilll hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT riordanm hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT tiany hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT bullocka hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT welfordr hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT elkinsj hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT oldhamn hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT bhattacharyas hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT gleadlej hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT ratcliffep hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT pughc hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily AT schofieldc hypoxiainduciblefactorhifasparaginehydroxylaseisidenticaltofactorinhibitinghiffihandisrelatedtothecupinstructuralfamily |