Mechanical forces play critical roles in the regulation of biological functions. For example, the environment pushing and pulling on cells can change their development, affect their movement, and help seal wounds after injury. Incorrect responses to mechanical inputs can lead to human disease, including cancer and blood clots. In biological systems, proteins sense forces by undergoing changes in their 3D conformation when external forces act. These changes, in turn can trigger other signaling events.
Despite its importance, the mechanical regulation at the fundamental level of single-proteins remains poorly understood, in part due to a lack of suitable techniques. To understand mechanical regulation in proteins, we need to probe very small forces, down to 1 pN, i.e. 1/1,000,000,000,000 of the weight of a chocolate bar.
The project ProForce wants to understand the mechanical regulation at the level of individual proteins in the previously inaccessible regime of very low forces to, ultimately, develop ways to directly interfere with and correct incorrect responses to forces. By probing proteins involved in several human diseases, we want to better understand the molecular basis of disease and to develop approaches to treat them. For this purpose, use so-called magnetic tweezers, which are a powerful tool to manipulate individual molecules by attaching them with one end to a surface and with the other end to a magnetic bead. Using a microscope connected to a camera, not too different from the ones in smart phones, we can track many molecules at the same time, which helps to generate measurement statistics. We complement magnetic tweezers with other experimental approaches, including fluorescence, X-rays, and other imaging techniques. The aim of ProForce is to understand mechano-regulation at the single-protein level and to establish force response as a potential drug target.
