A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
The Regulation Mechanism for the Auto-Inhibition of Binding of Human Filamin A to Integrin
Tekijät: Pentikainen U, Ylanne J
Kustantaja: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Julkaisuvuosi: 2009
Journal: Journal of Molecular Biology
Tietokannassa oleva lehden nimi: JOURNAL OF MOLECULAR BIOLOGY
Lehden akronyymi: J MOL BIOL
Vuosikerta: 393
Numero: 3
Aloitussivu: 644
Lopetussivu: 657
Sivujen määrä: 14
ISSN: 0022-2836
DOI: https://doi.org/10.1016/j.jmb.2009.08.035
Tiivistelmä
The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Human filamins are large actin cross-linking proteins that connect integrins to the cytoskeleton. Filamin binding to the cytoplasmic tail of beta integrins has been shown to prevent integrin activation m cells, which is important for controlling cell adhesion and migration. The molecular-level mechanism for filamin binding to integrin has been unclear, however, as it was recently demonstrated that filamin undergoes intramolecular auto-inhibition of integrin binding. In this study, using steered molecular dynamics simulations, we found that mechanical force applied to filamin can expose cryptic integrin binding sites. The forces required for this are considerably lower than those for filamin immunoglobulin domain unfolding. The mechanical-force-induced unfolding of filamin and exposure of integrin binding sites occur through stable intermediates where integrin binding is possible. Accordingly, our results support filamin's role as a mechanotransducer, since force-induced conformational changes allow binding of integrin and other transmembrane and intracellular proteins. This observed force-induced conformational change can also be one of possible mechanisms involved in the regulation of integrin activation. (c) 2009 Elsevier Ltd. All rights reserved.
The ability of adhesion receptors to transmit biochemical signals and mechanical force across cell membranes depends on interactions with the actin cytoskeleton. Human filamins are large actin cross-linking proteins that connect integrins to the cytoskeleton. Filamin binding to the cytoplasmic tail of beta integrins has been shown to prevent integrin activation m cells, which is important for controlling cell adhesion and migration. The molecular-level mechanism for filamin binding to integrin has been unclear, however, as it was recently demonstrated that filamin undergoes intramolecular auto-inhibition of integrin binding. In this study, using steered molecular dynamics simulations, we found that mechanical force applied to filamin can expose cryptic integrin binding sites. The forces required for this are considerably lower than those for filamin immunoglobulin domain unfolding. The mechanical-force-induced unfolding of filamin and exposure of integrin binding sites occur through stable intermediates where integrin binding is possible. Accordingly, our results support filamin's role as a mechanotransducer, since force-induced conformational changes allow binding of integrin and other transmembrane and intracellular proteins. This observed force-induced conformational change can also be one of possible mechanisms involved in the regulation of integrin activation. (c) 2009 Elsevier Ltd. All rights reserved.
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