This research addresses a fundamental question in cell biology: How do cells detect mechanical stress in the actin cytoskeleton? The internal cytoskeletal tension is modulated by the mechanical properties of its external environment. Cytoskeletal tension can be an internal representation the mechanical properties of its local environment that can be ?read? by the biochemical machinery. In fact proteins can be stretched by mechanical forces to reveal new binding sites, the recognition of these newly revealed binding sites by ?sensor? proteins is one possible way of detecting mechanical information. The LIM superfamily represents a large number of putative mechanosensitive cellular proteins that detect stress by a completely unknown mechanism.
I aim to identify the sequence determinants within the LIM domain responsible for detection of mechanical stress in the actin cytoskeleton. I then aim to discover the molecular mechanisms by which LIM domain proteins detect this stress, including identifying what LIM domains bind to and the nature of the deformation in the actin cytoskeleton. Revealing the mechanism of how a single member of this family detects cytoskeletal deformations will likely be generalizable to a large number of proteins. This will also drive future research involving how mechanosensitivity of each LIM protein is tuned and specificity achieved.
Mechanical forces in the environment have large effects on processes such as cell division, apoptosis and differentiation. Changes in the mechanics of the environment or defects in the cellular mechanoresponse are involved in a plethora of diseases including atherosclerosis, heart failure and cancer. A major challenge in the field is understanding mechanotransduction - the mechanisms by which mechanical information is detected and communicated to pathways that control cell behavior. Proteins containing LIM domains represent a large family of tension sensitive factors that detect mechanical stress to mount cellular responses; however, they detect these stresses by a completely unknown mechanism. Understanding how LIM domains function to detect and transmit information about mechanical stress will result in a deeper understanding of mechanotransduction, which is important for developing strategies of disease treatment and organ regeneration.