Breaking ties that bind biomolecules brings a surprising jump

Biological cells stick together. Their glue, in the form of ligands, forms protein complexes with biomolecules to serve a variety of purposes, such as cell anchoring, migration, signaling and division. Cell adhesion complexes (CACs), activated by ligand binding, can rupture. This loss of cell adhesion and rupturing can contribute to cancer cell metastases.

Lymphocyte function-associated antigen 1 (LFA-1), found on all T-cells (immune system cells) as well as several other cell types, is involved in immune system recruitment to infection sites as it binds to the intercellular adhesion molecule 1(ICAM-1) on antigen-presenting cells. To better understand and quantify how this binding ruptures, the researchers modeled the system with an adapted self-organizing polymer model that predicts and interprets unfolding pathways of proteins. They found that the force used to break ligands binding LFA-1 and ICAM into a CAC created two “brittle states” between them — described by having a fixed transition state over a range of forces — with the dynamics of the rupture switching sharply from one brittle state to another.

Describing their theory and simulations in The Journal of Chemical Physics, the authors were surprised to discover unusual rupture mechanics involved two transition states: one appearing at high forces, and one at low forces. The unusual shift between two brittle states is not found when rupturing other protein complexes. Significantly, their work revealed a new rupture mechanism in which the brittleness jumps abruptly.

The response of cell adhesion complexes to mechanical force varies, and these results offer the valuable molecular interpretations that can differentiate between rupture mechanisms captured experimentally. The researchers will carry out further simulations to see if this mechanism of ligand rupture is applicable to other protein complexes related to cancer.

Source: “Forced-rupture of cell-adhesion complexes reveals abrupt switch between two brittle states,” by Ngo Minh Toan and D. Thirumalai, The Journal of Chemical Physics (2018). The article can be accessed at https://doi.org/10.1063/1.5011056 .