TY  - GEN
CY  - Heidelberg
TI  - Exploring Mechanical Signaling at Cellular Force
Transduction Hubs using Molecular Simulations
AV  - public
Y1  - 2022///
ID  - heidok32149
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/32149/
N2  - Cells are subjected to mechanical forces and must sense and adequately react to them in order to develop and survive ? a process known as mechanotransduction. This conversion of mechanical into biochemical signals is clustered at mechanotransduction hubs, i.e. protein complexes specialized for this purpose. Two examples of such hubs are on the one hand focal adhesions at the plasma membrane, which mediate signaling of the cellular inside with the outside matrix, and on the other hand the kinetochores, which control the proper segregation of chromosomes during cell division. In this work, I primarily used molecular dynamics simulations to investigate one protein from each of these two mechanotransduction hubs to further decipher their mechanisms for transducing mechanical signals.
For the crucial focal adhesion component Integrin-linked Kinase (ILK) I elucidated a non-conventional function of ATP-binding to the pseudokinase ILK. ATP promotes the structural stability of ILK and allosterically influences the interaction between ILK and its binding partner parvin, which leads to enhanced mechanoresistance of the ILK:parvin complex. Cell-level experiments from collaborators demonstrated that these features result in focal adhesion stabilization and proper traction force buildup, whichmanifests itself in efficient cell  migration. Combined, these results suggest that ILK, stabilized and altered by the presence of ATP, might be capable to function as an active mechanotransducer.
The partially disordered inner centromere protein (INCENP), on the other hand, is a passive participant in mechanotransduction at kinetochores. I detected that its disordered region transitions from globular to coil states in response to phosphorylation, which considerably tunes its length and may influence its phase separation properties. These features would allow INCENP to act as length-variable tether to regulate the activity of the chromosome segregation kinase Aurora B by controlling Aurora B?s access to targets in response to kinetochore tension.
My work thus sheds light on two widely different mechanisms by which non-enzymatic scaffold proteins are involved in mechanotransduction. In this way, we are expanding our palette of the manifold principles of mechanical signaling and thereby coming closer to grasping the complexity of cells.
A1  - Kemmer, Isabel Marina
ER  -