ERM protein family

ERM protein family refers to a group of proteins that play a crucial role in the linkage of the cell membrane to the actin cytoskeleton. This family includes three closely related proteins: ezrin, radixin, and moesin, which are collectively known as the ERM proteins. These proteins are involved in various cellular processes, including the maintenance of cell shape, adhesion, and signaling. They are also implicated in the development and progression of certain diseases, including cancer.

Function

ERM proteins act as cross-linkers between the plasma membrane and the actin cytoskeleton, playing a pivotal role in the structural organization of the cell surface and in signal transduction pathways. They are activated by phosphorylation, which leads to a conformational change that exposes their actin-binding site and their membrane association domain, allowing them to interact with both the membrane and the cytoskeleton. This interaction is essential for the stabilization of cell surface structures, such as microvilli in epithelial cells, and for the regulation of cell shape, motility, and adhesion.

Structure

The ERM proteins share a common structure comprising three domains: the N-terminal FERM domain, which is involved in binding to the plasma membrane; a central α-helical domain; and a C-terminal domain, which interacts with F-actin. The FERM domain is subdivided into three subdomains (F1, F2, and F3), which together form a cloverleaf structure. The F3 subdomain is primarily responsible for the interaction with membrane proteins, such as CD44 and ICAM-2.

Regulation

The activity of ERM proteins is regulated by phosphorylation and dephosphorylation mechanisms. Phosphorylation of a conserved threonine residue in the C-terminal domain is critical for the activation of ERM proteins. This modification induces a conformational change that disrupts the intramolecular association between the N-terminal and C-terminal domains, leading to the exposure of the actin-binding site and the membrane association domain. Dephosphorylation, on the other hand, leads to the inactivation of ERM proteins and the reformation of the intramolecular association, rendering them inactive.

Clinical Significance

Alterations in the expression and function of ERM proteins have been associated with various pathological conditions, including cancer. Overexpression of ezrin, for example, has been linked to the progression and metastasis of osteosarcoma and other types of cancer. ERM proteins are also involved in the regulation of the immune response, and their dysfunction can lead to immune-related diseases.

Research Directions

Current research on ERM proteins focuses on understanding their precise roles in cellular processes and disease mechanisms. This includes investigating the regulatory mechanisms that control their activity, their interactions with other cellular components, and their potential as therapeutic targets in diseases such as cancer.