Tetraspanins (TSPANs) are a family of transmembrane proteins involved in various important cellular functions such as cell adhesion, migration, signaling, and membrane fusion. To exert their functions, TSPANs form higher-order structures in the form of nanoscopic or microscopic domains. The assembly of TSPANs probably depends on their membrane concentration, which increases in curved membranes for some TSPANs because of their membrane curvature sensitivity. Understanding which parts of the proteins govern their curvature sensitivity and interactions is essential for elucidating tetraspanin dynamics and function.
The cover image depicts an artistic representation of an experiment in which a giant plasma membrane vesicle, consisting of a mixture of lipids and proteins, is held in a micropipette. On the other side of the vesicle, a membrane tube is extracted by using a microsphere held by an optical trap. The curvature of the membrane tube is modulated by the aspiration pressure in the micropipette. The vesicle and tube are imaged by using confocal fluorescence microscopy. Green blobs depict the proteins, and red molecules are lipophilic fluorophores. The illustration shows the enrichment of the protein within the curved tube.
In our study, we focused on a particular protein called TSPAN4, which plays a critical role in the formation of migrasomes and is involved in membrane damage repair. We tested the enrichment of the proteins within curved tubes and their redistribution after tension decrease and tube enlargement. By using proteins mutated in different positions, we pinpointed the part of the TSPAN4 protein essential for curvature sensitivity and curvature-induced interactions. This part, called the “extracellular 2 domain,” might regulate TSPAN proteins by determining their level of enrichment in curved membranes and governing their interactions with other molecules. Therefore, this region is possibly crucial for modulating the biological functions of TSPANs.
— Raviv Dharan, Alisa Vaknin, and Raya Sorkin