eprintid: 1466171
rev_number: 43
eprint_status: archive
userid: 608
dir: disk0/01/46/61/71
datestamp: 2015-04-16 15:40:58
lastmod: 2021-10-04 00:55:34
status_changed: 2015-04-16 15:40:57
type: article
metadata_visibility: show
item_issues_count: 0
creators_name: Doro, F
creators_name: Saladino, G
creators_name: Belvisi, L
creators_name: Civera, M
creators_name: Gervasio, FL
title: New Insights into the Molecular Mechanism of E-Cadherin-Mediated Cell Adhesion by Free Energy Calculations
ispublished: pub
divisions: UCL
divisions: B04
divisions: C06
divisions: F56
note: This document is the Accepted Manuscript version of a Published Work that appeared in final form in     Journal of Chemical Theory and Computation, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/ct5010164
abstract: Three-dimensional domain swapping is an important mode of protein association leading to the formation of stable dimers. Monomers associating via this mechanism mutually exchange a domain to form a homodimer. Classical cadherins, an increasingly important target for anticancer therapy, use domain swapping to mediate cell adhesion. However, despite its importance, the molecular mechanism of domain swapping is still debated. Here, we study the conformational changes that lead to activation and dimerization via domain swapping of E-cadherin. Using state-of-the-art enhanced sampling atomistic simulations, we reconstruct its conformational free energy landscape, obtaining the free energy profile connecting the inactive and active form. Our simulations predict that the E-cadherin monomer populates the open and closed forms almost equally, which is in agreement with the proposed “selected fit” mechanism in which monomers in an active conformational state bind to form a homodimer, analogous to the conformational selection mechanism often observed in ligand–target binding. Moreover, we find that the open state population is increased in the presence of calcium ions at the extracellular boundary, suggesting their possible role as allosteric activators of the conformational change.
date: 2015-03-03
official_url: http://dx.doi.org/10.1021/ct5010164
vfaculties: VMPS
oa_status: green
full_text_type: other
language: eng
primo: open
primo_central: open_green
article_type_text: article
verified: verified_manual
elements_source: Manually entered
elements_id: 1026399
doi: 10.1021/ct5010164
lyricists_name: Gervasio, Francesco Luigi
lyricists_name: Saladino, Giorgio
lyricists_id: FLGER36
lyricists_id: GSALA75
full_text_status: public
publication: Journal of Chemical Theory and Computation
volume: 11
article_number: 4
pagerange: 1354 - 1359
issn: 1549-9618
citation:        Doro, F;    Saladino, G;    Belvisi, L;    Civera, M;    Gervasio, FL;      (2015)    New Insights into the Molecular Mechanism of E-Cadherin-Mediated Cell Adhesion by Free Energy Calculations.                   Journal of Chemical Theory and Computation , 11     , Article 4.  10.1021/ct5010164 <https://doi.org/10.1021/ct5010164>.       Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/1466171/1/Revised_manuscript.pdf