‘One Ring to Rule Them All’: How Actin Filaments Are Assembled by Formins
Actin is a highly abundant protein that controls the shape and movement of all our cells. It performs this vital role by steadily assembling into filaments, one actin molecule at a time. The proteins of the formin family are crucial partners in this process. Positioned at the filament end, they recruit new actin subunits and remain associated with the end by ‘stepping’ with the growing filament. There are as many as 15 different formins in our cells that drive actin filament growth at different speeds and for various purposes.
The Elusive Mechanism of Formins
Despite their significance, the exact mechanism of action of formins and the basis for their different inherent speeds have remained elusive. Now, for the first time, researchers from the groups of Stefan Raunser and Peter Bieling at the Max Planck Institute of Molecular Physiology in Dortmund have visualized at the molecular level how formins bind to the ends of actin filaments. This pioneering work allowed them to uncover how formins enable the addition of new actin molecules to a growing filament. Moreover, they unraveled the reasons behind the varying speeds at which different formins promote this process.
A Combination of Techniques
The MPI researchers employed a combination of innovative biochemical strategies and electron cryo-microscopy (cryo-EM) to achieve this breakthrough, published in the prestigious journal Science. This transformative research has significant implications, helping us comprehend why certain mutations in formins can lead to neurological, immune, and cardiovascular diseases.
The ‘Ring’ Structure of Formins
Formins are aptly named due to their characteristic ring-like structure. Imagine a tiny doughnut-shaped protein. This unique architecture allows formins to encircle the actin filament, providing a secure grip as the filament grows. As new actin molecules are added, the formin ‘steps’ along the filament, retaining its firm hold.
Speed Differences Explained
The researchers discovered that the speed at which formins promote actin filament growth is dictated by the flexibility of the formin’s ring structure. More flexible rings allow for quicker ‘stepping,’ resulting in faster filament growth. Conversely, stiffer rings hinder movement, leading to slower filament growth. This discovery provides a mechanistic explanation for the varying speeds observed among different formins.
Implications for Human Health
“Our research provides fundamental insights into the molecular mechanisms underlying actin filament assembly,” says Stefan Raunser, Director at the Max Planck Institute of Molecular Physiology. “Understanding these mechanisms is crucial for deciphering the development of diseases caused by mutations in formins.” For instance, mutations in formins have been linked to a range of conditions, including inherited deafness, immune deficiencies, and certain types of cancer.
A Stepping Stone for Future Research
This groundbreaking study lays the foundation for future research, paving the way for a deeper understanding of formin biology and its implications for human health. As we continue to unravel the intricate workings of these fascinating proteins, we can anticipate advancements in drug development and therapeutic strategies for diseases associated with formin dysfunction.