A new study, appearing in the journal Cell, has provided pivotal new understandings of how actin filaments come apart. This process is critical for allowing cells to migrate. Stefan Raunser, director of the Max Planck Institute of Molecular Physiology in Dortmund, Germany, heads such a team. Their research illustrates in detail the collaborative action between three proteins—coronin, cofilin and AIP1—in promoting anti-assembly and regulating actin dynamics. Parsing these molecular interactions is key to understanding the way normal and cancerous cells move through the body.
The new study’s findings illuminate that breaking down actin filaments is a complicated, multi-step process. Each of these steps must work in concert to ensure effective cellular locomotion. Cells may migrate at fast rates on the order of 30–50 micrometers /hr, yielding a potential total migration distance of 1 mm per day. This motion is key for a startling range of biological processes, from wound healing to immune response.
Key Players in Actin Dynamics
Coronin is the major protein of interest underscored by this study. It binds to actin filaments and promotes a release of inorganic phosphate that accumulates on actin post ATP hydrolysis. This step is critical to getting the disassembly process underway. Next, cofilin binds to the actin filament, pushing coronin away off the filament and creating a binding surface for AIP1.
“Our structural study enabled us to redefine the roles of the key factors in actin filament disassembly,” – Stefan Raunser
Once AIP1 binds to the filament, it’s no longer a simple tab clamp—it’s a double-fingered tab clamp, gripping and squeezing the actin structure. This action disrupts not just a stable actin filament, but the binding sites of a periodic lattice. Consequently, the filaments are quickly broken down. The joint work of these proteins orchestrates a very dynamic process that is crucial for cell crawling.
Visualization of Molecular Processes
The scientists used cutting-edge cryo-electron microscopy approaches to obtain near-atomic resolution 3D structures of the proteins central to this process. Through this groundbreaking technique, they were able to record actin filament disassembly in unparalleled detail.
“Using cryo-electron microscopy, we obtained 16 3D structures that show how these proteins act together on actin filaments,” – Wout Oosterheert
To help explain the fascinating interactions between coronin, cofilin, and AIP1, the researchers illustrated their interactions as a dynamic “dance.” This fascinating molecular ballet holds the key to understanding how and why cells migrate. This integrative approach deepens our understanding of actin dynamics and harbors a great promise for future therapeutic advances.
Implications for Health and Disease
This study extends beyond the confines of fundamental biology. By untangling the precise mechanisms behind how cells migrate, we can discover novel therapeutic approaches. This elucidation represents a powerful new framework for understanding actin dynamics. This discovery might one day allow us to more effectively target cancer metastasis and other diseases characterized by unregulated cell movement.
“Our work now provides a mechanistic framework for actin dynamics which may ultimately contribute to the development of new therapeutic agents,” – Wout Oosterheert
In one context, cells may appear to proceeding at a glacial pace, moving only about 1 mm per day on average. The incredible molecular processes going on inside of them move at light-speed. Raunser noted that “the molecular process underlying the movement, however, must occur at ‘breakneck’ speed,” emphasizing the complexity and efficiency of cellular mechanisms.