Aspartate/asparagine-β-hydroxylase crystal structures reveal an unexpected epidermal growth factor-like domain substrate disulfide pattern

Inga Pfeffer, Lennart Brewitz, Tobias Krojer, Sacha A. Jensen, Grazyna T. Kochan, Nadia J. Kershaw, Kirsty S. Hewitson, Luke A. McNeill, Holger Kramer, Martin Münzel, Richard J. Hopkinson, Udo Oppermann, Penny A. Handford, Michael A. McDonough and Christopher J. Schofield ()
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Inga Pfeffer: University of Oxford
Lennart Brewitz: University of Oxford
Tobias Krojer: University of Oxford
Sacha A. Jensen: University of Oxford
Grazyna T. Kochan: University of Oxford
Nadia J. Kershaw: University of Oxford
Kirsty S. Hewitson: University of Oxford
Luke A. McNeill: University of Oxford
Holger Kramer: University of Oxford
Martin Münzel: University of Oxford
Richard J. Hopkinson: University of Oxford
Udo Oppermann: University of Oxford
Penny A. Handford: University of Oxford
Michael A. McDonough: University of Oxford
Christopher J. Schofield: University of Oxford

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12711-7

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