Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern
AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we...
| Автори: | , , , , , , , , , , , , , , |
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| Формат: | Journal article |
| Мова: | English |
| Опубліковано: |
Nature Research
2019
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| _version_ | 1826258331077967872 |
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| author | Pfeffer, I Brewitz, L Krojer, T Jensen, SA Kochan, GT Kershaw, NJ Hewitson, KS McNeill, LA Kramer, H Münzel, M Hopkinson, RJ Oppermann, U Handford, PA McDonough, MA Schofield, CJ |
| author_facet | Pfeffer, I Brewitz, L Krojer, T Jensen, SA Kochan, GT Kershaw, NJ Hewitson, KS McNeill, LA Kramer, H Münzel, M Hopkinson, RJ Oppermann, U Handford, PA McDonough, MA Schofield, CJ |
| author_sort | Pfeffer, I |
| collection | OXFORD |
| description | AspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1–3, 2–4, 5–6 disulfide bonding pattern; an unexpected Cys3–4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases. |
| first_indexed | 2024-03-06T18:32:18Z |
| format | Journal article |
| id | oxford-uuid:0a1194dd-a9fc-4cd5-9390-46c2c68e9f33 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T18:32:18Z |
| publishDate | 2019 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:0a1194dd-a9fc-4cd5-9390-46c2c68e9f332022-03-26T09:21:52ZAspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide patternJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:0a1194dd-a9fc-4cd5-9390-46c2c68e9f33EnglishSymplectic Elements at OxfordNature Research2019Pfeffer, IBrewitz, LKrojer, TJensen, SAKochan, GTKershaw, NJHewitson, KSMcNeill, LAKramer, HMünzel, MHopkinson, RJOppermann, UHandford, PAMcDonough, MASchofield, CJAspH is an endoplasmic reticulum (ER) membrane-anchored 2-oxoglutarate oxygenase whose C-terminal oxygenase and tetratricopeptide repeat (TPR) domains present in the ER lumen. AspH catalyses hydroxylation of asparaginyl- and aspartyl-residues in epidermal growth factor-like domains (EGFDs). Here we report crystal structures of human AspH, with and without substrate, that reveal substantial conformational changes of the oxygenase and TPR domains during substrate binding. Fe(II)-binding by AspH is unusual, employing only two Fe(II)-binding ligands (His679/His725). Most EGFD structures adopt an established fold with a conserved Cys1–3, 2–4, 5–6 disulfide bonding pattern; an unexpected Cys3–4 disulfide bonding pattern is observed in AspH-EGFD substrate complexes, the catalytic relevance of which is supported by studies involving stable cyclic peptide substrate analogues and by effects of Ca(II) ions on activity. The results have implications for EGFD disulfide pattern processing in the ER and will enable medicinal chemistry efforts targeting human 2OG oxygenases. |
| spellingShingle | Pfeffer, I Brewitz, L Krojer, T Jensen, SA Kochan, GT Kershaw, NJ Hewitson, KS McNeill, LA Kramer, H Münzel, M Hopkinson, RJ Oppermann, U Handford, PA McDonough, MA Schofield, CJ Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern |
| title | Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern |
| title_full | Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern |
| title_fullStr | Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern |
| title_full_unstemmed | Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern |
| title_short | Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern |
| title_sort | aspartate asparagine β hydroxylase crystal structures reveal an unexpected epidermal growth factor like domain substrate disulfide pattern |
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