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

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Inga Pfeffer ◽  
Lennart Brewitz ◽  
Tobias Krojer ◽  
Sacha A. Jensen ◽  
Grazyna T. Kochan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Conformational Changes ◽  
Cyclic Peptide ◽  
Tetratricopeptide Repeat ◽  
Disulfide Bonding ◽  
Pattern Processing ◽  
Substrate Analogues ◽  
Epidermal Growth

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.

scholarly journals Single-Molecule Investigation of Conformational Changes in Epidermal Growth Factor Receptor

2020 ◽  
Vol 118 (3) ◽  
pp. 188a
Author(s):  
Raju Regmi ◽  
Shwetha Srinivasan ◽  
Xingcheng Lin ◽  
Steven Quinn ◽  
Wei He ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Single Molecule ◽  
Conformational Changes ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Factor inhibiting hypoxia-inducible factor (FIH) and other asparaginyl hydroxylases

2004 ◽  
Vol 32 (6) ◽  
pp. 943-945 ◽  
Author(s):  
D.E. Lancaster ◽  
M.A. McDonough ◽  
C.J. Schofield
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Hypoxia Inducible Factor ◽  
Binding Motif ◽  
Iron Binding ◽  
Sequence Analyses ◽  
Hypoxic Response ◽  
Epidermal Growth

FIH (Factor inhibiting hypoxia-inducible factor), an asparaginyl β-hydroxylase belonging to the super-family of 2-oxoglutarate and Fe(II)-dependent dioxygenases, catalyses hydroxylation of Asn-803 of hypoxia-inducible factor, a transcription factor that regulates the mammalian hypoxic response. Only one other asparaginyl β-hydroxylase, which catalyses hydroxylation of both aspartyl and asparaginyl residues in EGF (epidermal growth factor)-like domains, has been characterized. In the light of recent crystal structures of FIH, we compare FIH with the EGFH (EGF β-hydroxylase) and putative asparagine/asparaginyl hydroxylases. Sequence analyses imply that EGFH does not contain the HXD/E iron-binding motif characteristic of most of the 2-oxoglutarate oxygenases.

scholarly journals A cyclic peptide derived from α-fetoprotein inhibits the proliferative effects of the epidermal growth factor and estradiol in MCF7 cells

2008 ◽  
Author(s):  
Walter Sierralta ◽  
Luis Valladares ◽  
Ana Pino ◽  
Maráa Epuñán ◽  
Elmer Antileo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cyclic Peptide ◽  
Mcf7 Cells ◽  
Epidermal Growth

scholarly journals Structure and Clinical Relevance of the Epidermal Growth Factor Receptor in Human Cancer

2008 ◽  
Vol 26 (10) ◽  
pp. 1742-1751 ◽  
Author(s):  
Amit Kumar ◽  
Edward T. Petri ◽  
Balazs Halmos ◽  
Titus J. Boggon
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Human Cancer ◽  
Growth Factor Receptor ◽  
Kinase Domain ◽  
Atomic Level ◽  
Epidermal Growth ◽  
Egfr Kinase

Purpose To review the recent advances in the atomic-level understanding of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK). We aim to highlight the current and future importance of these studies for the understanding and treatment of malignancies where EGFR-TK is improperly activated. Methods The analysis was conducted on published crystal structures deposited in the Protein Data Bank ( www.pdb.org ) using the program O. Results In this review we emphasize how recent EGFR kinase domain crystal structures can explain the mechanisms of activation for L858R and other EGFR-TK mutations, and compare these distinct activating mechanisms with those recently described for the wild-type EGFR. We suggest an atomic-level mechanism for the poor efficacy of lapatinib against tumors with activating EGFR kinase domain point mutations compared with the efficacy of gefitinib and erlotinib, and demonstrate how structural insights help our understanding of acquired resistance to these agents. We also highlight how these new molecular-level structural data are expected to affect the development of EGFR-TK targeted small molecule kinase inhibitors. Conclusion There are now more crystal structures published for the EGFR-TK domain than for any other TK. This wealth of crystallographic information is beginning to describe the mechanisms by which proper regulation of EGFR-TK is lost in disease. These crystal structures are beginning to show how small molecules inhibit EGFR-TK activity and will aid development of EGFR-TK mutant targeted therapies.

scholarly journals A perspective on structural and mechanistic aspects of protein O-fucosylation

2018 ◽  
Vol 74 (8) ◽  
pp. 443-450 ◽  
Author(s):  
Erandi Lira-Navarrete ◽  
Ramon Hurtado-Guerrero
Keyword(s):  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Crystal Structures ◽  
Structural Information ◽  
Type I ◽  
Post Translational Modification ◽  
Protein Substrates ◽  
The Past ◽  
Epidermal Growth ◽  
Catalytic Mechanisms

Protein O-fucosylation is an important post-translational modification (PTM) found in cysteine-rich repeats in proteins. Protein O-fucosyltransferases 1 and 2 (PoFUT1 and PoFUT2) are the enzymes responsible for this PTM and selectively glycosylate specific residues in epidermal growth factor-like (EGF) repeats and thrombospondin type I repeats (TSRs), respectively. Within the past six years, crystal structures of both enzymes have been reported, revealing important information on how they recognize protein substrates and achieve catalysis. Here, the structural information available today is summarized and how PoFUT1 and PoFUT2 employ different catalytic mechanisms is discussed.

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