Distinctive binding of three antagonistic peptides to the ephrin-binding pocket of the EphA4 receptor

Lamberto, Ilaria, Qin, Haina, Noberini, Roberta, Premkumar, Lakshmanane, Bourgin, Caroline, Riedl, Stefan J., Song, Jianxing and Pasquale, Elena B. (2012) Distinctive binding of three antagonistic peptides to the ephrin-binding pocket of the EphA4 receptor. Biochemical Journal, 445 47-56. doi:10.1042/BJ20120408


Author Lamberto, Ilaria
Qin, Haina
Noberini, Roberta
Premkumar, Lakshmanane
Bourgin, Caroline
Riedl, Stefan J.
Song, Jianxing
Pasquale, Elena B.
Title Distinctive binding of three antagonistic peptides to the ephrin-binding pocket of the EphA4 receptor
Journal name Biochemical Journal   Check publisher's open access policy
ISSN 0264-6021
1470-8728
Publication date 2012-07-01
Year available 2012
Sub-type Article (original research)
DOI 10.1042/BJ20120408
Volume 445
Start page 47
End page 56
Total pages 10
Place of publication London, United Kingdom
Publisher Portland Press Ltd.
Language eng
Formatted abstract
The EphA4 receptor tyrosine kinase interacts with ephrin ligands to regulatemany processes, ranging from axon guidance and nerve regeneration to cancer malignancy. Thus antagonists that inhibit ephrin binding to EphA4 could be useful for a variety of research and therapeutic applications. In the present study we characterize the binding features of three antagonistic peptides (KYL,APYand VTM) that selectively target EphA4 among the Eph receptors. Isothermal titration calorimetry analysis demonstrated that all three peptides bind to the ephrin-binding domain of EphA4 with low micromolar affinity. Furthermore, the effects of a series of EphA4 mutations suggest that the peptides interact in different ways with the ephrin-binding pocket of EphA4. Chemical-shift changes observed by NMR spectroscopy upon binding of the KYL peptide involve many EphA4 residues, consistent with extensive interactions and possibly receptor conformational changes. Additionally, systematic replacement of each of the 12 amino acids of KYL and VTM identify the residues critical for EphA4, binding. The peptides exhibit a long half-life in cell culture medium which, with their substantial binding affinity and selectivity for EphA4, makes them excellent research tools to modulate EphA4 function.
Keyword Antagonist
Cancer
Ephrin
Imaging
Nerve regeneration
Receptor Tyrosine Kinase
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Non HERDC
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 26 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 26 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 01 Nov 2013, 03:05:19 EST by Prem Lakshmanane on behalf of Institute for Molecular Bioscience