Mechanobiology of Intercellular Interactions

Our research on mechanobiology of intercellular interactions consists of:

1. Lymphocyte adhesion mediated by integrins

Integrin is a heterodimeric membrane receptor that is expressed on most eukaryotic cells and serves as an adhesion receptor and mechanical sensor to transmit signals bidirectionally across the plasma membrane. Using atomic force microscopy (AFM), we examined an allosteric regulatory model through which the ligand-binding affinity can be increased rapidly when a force is allowed to stretch the C-terminal of integrin’s ligand-binding I-domain (20). This type of mechanism may account for the rapid ligand affinity adjustment during leukocyte migration. More recently, we studied how integrin-ligand bond lifetime and mechanical properties are regulated on lymphocytes by chemokine signals.

2. Virushost cell interaction

We have extended our single-molecular force spectroscopy to virus–host cell interactions. In one project, we collaborated with Dr. Tione Buranda at the University of New Mexico and discovered the role of integrin in mediating hantavirus interaction with endothelial cells. We demonstrated that a low-affinity cis interaction between β3 integrin and cell surface receptor P2Y2R provides allosteric resistance to the normal membrane motion associated with the global conformational change required for integrin activation. The binding of the hantavirus with the integrin’s plexin-semaphorin-integrin (PSI) domain results in integrin activation and the dissociation of integrin from P2Y2R. Termination of the tensile force on the integrin results in endocytosis of the integrin together with the virus. The study reveals a new mechanism for integrin activation after the binding of the hantavirus to the integrin’s PSI domain. The findings have potential impact for the discovery of novel therapeutic targets of hantavirus infection, due to a high mortality ratio. A manuscript on this discovery has been accepted for publication by Molecular Biology of the Cell (22).