A potential new, stable state of the E-cadherin strand-swapped dimer in solution

Schumann-Gillett, A; Mark, AE; Deplazes, E; O’Mara, ML

A potential new, stable state of the E-cadherin strand-swapped dimer in solution

Schumann-Gillett, A Mark, AE Deplazes, E

O’Mara, ML

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Publication Type:: Journal Article
Citation:: European Biophysics Journal, 2018, 47 (1), pp. 59 - 67
Issue Date:: 2018-01-01

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Field	Value	Language
dc.contributor.author	Schumann-Gillett, A	en_US
dc.contributor.author	Mark, AE	en_US
dc.contributor.author	Deplazes, E https://orcid.org/0000-0003-2052-5536	en_US
dc.contributor.author	O’Mara, ML	en_US
dc.date.available	2017-06-05	en_US
dc.date.issued	2018-01-01	en_US
dc.identifier.citation	European Biophysics Journal, 2018, 47 (1), pp. 59 - 67	en_US
dc.identifier.issn	0175-7571	en_US
dc.identifier.uri	http://hdl.handle.net/10453/130258
dc.description.abstract	© 2017, European Biophysical Societies' Association. E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution.	en_US
dc.relation.ispartof	European Biophysics Journal	en_US
dc.relation.isbasedon	10.1007/s00249-017-1229-3	en_US
dc.subject.classification	Biophysics	en_US
dc.subject.mesh	Cadherins	en_US
dc.subject.mesh	Solutions	en_US
dc.subject.mesh	Protein Structure, Quaternary	en_US
dc.subject.mesh	Protein Multimerization	en_US
dc.subject.mesh	Protein Stability	en_US
dc.subject.mesh	Molecular Dynamics Simulation	en_US
dc.title	A potential new, stable state of the E-cadherin strand-swapped dimer in solution	en_US
dc.type	Journal Article
utslib.citation.volume	1	en_US
utslib.citation.volume	47	en_US
utslib.for	0299 Other Physical Sciences	en_US
utslib.for	0202 Atomic, Molecular, Nuclear, Particle and Plasma Physics	en_US
utslib.for	0601 Biochemistry and Cell Biology	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
utslib.copyright.status	open_access
pubs.issue	1	en_US
pubs.publication-status	Published	en_US
pubs.volume	47	en_US

Abstract:

© 2017, European Biophysical Societies' Association. E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution.

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http://hdl.handle.net/10453/130258