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This title appears in the Scientific Report : 2018 

On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation

On the contributing role of the transmembrane domain for subunit-specific sensitivity of integrin activation

Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential T...

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Personal Name(s): Pagani, Giulia
Gohlke, Holger (Corresponding author)
Contributing Institute: Strukturbiochemie; ICS-6
John von Neumann - Institut für Computing; NIC
Jülich Supercomputing Center; JSC
Published in: Scientific reports, 8 (2018) 1, S. 5733
Imprint: London Nature Publishing Group 2018
DOI: 10.1038/s41598-018-23778-5
PubMed ID: 29636500
Document Type: Journal Article
Research Program: Structure, energetics, and dynamics of integrin inside-out signaling
Physical Basis of Diseases
Functional Macromolecules and Complexes
Computational Science and Mathematical Methods
Link: OpenAccess
OpenAccess
Publikationsportal JuSER
Please use the identifier: http://dx.doi.org/10.1038/s41598-018-23778-5 in citations.
Please use the identifier: http://hdl.handle.net/2128/18073 in citations.

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Integrins are α/β heterodimeric transmembrane adhesion receptors. Evidence exists that their transmembrane domain (TMD) separates upon activation. Subunit-specific differences in activation sensitivity of integrins were reported. However, whether sequence variations in the TMD lead to differential TMD association has remained elusive. Here, we show by molecular dynamics simulations and association free energy calculations on TMDs of integrin αIIbβ3, αvβ3, and α5β1 that αIIbβ3 TMD is most stably associated; this difference is related to interaction differences across the TMDs. The order of TMD association stability is paralleled by the basal activity of these integrins, which suggests that TMD differences can have a decisive effect on integrin conformational free energies. We also identified a specific order of clasp disintegration upon TMD dissociation, which suggests that the closed state of integrins may comprise several microstates. Our results provide unprecedented insights into a possibly contributing role of TMD towards subunit-specific sensitivity of integrin activation.

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