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

DOI: 10.1038/s41467-019-12711-7 DOI Help

Authors: Inga Pfeffer (University of Oxford) , Lennart Brewitz (University of Oxford) , Tobias Krojer (Structural Genomics Consortium, University of Oxford) , Sacha A. Jensen (University of Oxford) , Grazyna T. Kochan (Structural Genomics Consortium, 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 (Structural Genomics Consortium, University of Oxford; NDORMS) , Penny A. Handford (University of Oxford) , Michael A. Mcdonough (University of Oxford) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 10

State: Published (Approved)
Published: October 2019

Open Access Open Access

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.

Subject Areas: Chemistry, Biology and Bio-materials

Instruments: I02-Macromolecular Crystallography , I04-Macromolecular Crystallography

Added On: 06/11/2019 11:36


Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)