Conformational Clamping by a Membrane Ligand Activates the EphA2 Receptor.

Autor: Westerfield JM; Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA., Sahoo AR; Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA., Alves DS; Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA., Grau B; Departament de Bioquímica i Biologia Molecular, Institut Universitari de Biotecnologia i Biomedicina (BIOTECMED), Universitat de València, E-46100 Burjassot, Spain., Cameron A; Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA., Maxwell M; Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA., Schuster JA; Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA., Souza PCT; Molecular Microbiology and Structural Biochemistry, UMR 5086 CNRS & University of Lyon, 7 Passage du Vercors, F-69367 Lyon, France., Mingarro I; Departament de Bioquímica i Biologia Molecular, Institut Universitari de Biotecnologia i Biomedicina (BIOTECMED), Universitat de València, E-46100 Burjassot, Spain., Buck M; Department of Physiology and Biophysics, Case Western Reserve University, School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA., Barrera FN; Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, 1311 Cumberland Avenue, Knoxville, TN 37996, USA. Electronic address: fbarrera@utk.edu.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2021 Sep 03; Vol. 433 (18), pp. 167144. Date of Electronic Publication: 2021 Jul 03.
DOI: 10.1016/j.jmb.2021.167144
Abstrakt: The EphA2 receptor is a promising drug target for cancer treatment, since EphA2 activation can inhibit metastasis and tumor progression. It has been recently described that the TYPE7 peptide activates EphA2 using a novel mechanism that involves binding to the single transmembrane domain of the receptor. TYPE7 is a conditional transmembrane (TM) ligand, which only inserts into membranes at neutral pH in the presence of the TM region of EphA2. However, how membrane interactions can activate EphA2 is not known. We systematically altered the sequence of TYPE7 to identify the binding motif used to activate EphA2. With the resulting six peptides, we performed biophysical and cell migration assays that identified a new potent peptide variant. We also performed a mutational screen that determined the helical interface that mediates dimerization of the TM domain of EphA2 in cells. These results, together with molecular dynamic simulations, allowed to elucidate the molecular mechanism that TYPE7 uses to activate EphA2, where the membrane peptide acts as a molecular clamp that wraps around the TM dimer of the receptor. We propose that this binding mode stabilizes the active conformation of EphA2. Our data, additionally, provide clues into the properties that TM ligands need to have in order to achieve activation of membrane receptors.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2021 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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