This title appears in the Scientific Report :
2018
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.
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 |
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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://hdl.handle.net/2128/18073 in citations.
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. |