One Ring to Govern Them All”: The Assembly Mechanism of Actin Filaments by Forming

Actin, a ubiquitous protein crucial for shaping and mobilizing our cells, orchestrates its function by progressively forming filaments, with each actin molecule joining the chain one by one. In this process, forming emerge as key players, stationed at the filament’s end to recruit new actin subunits and persistently engage with the growing structure.
Our cells harbor up to 15 distinct forming, each orchestrating actin filament growth at varying rates and for diverse purposes. Despite their essential role, the precise modus operandi of forming and the factors influencing their disparate speeds have long remained enigmatic.
In a groundbreaking revelation, researchers from the Max Planck Institute of Molecular Physiology in Dortmund, led by Stefan Raunser and Peter Bieling, have unveiled the molecular intricacies of how forming bind to actin filament ends, shedding light on their role in facilitating new actin molecule addition to the growing filament.
Employing a blend of biochemical techniques and electron cryo-microscopy (cryo-EM), the team achieved a milestone, capturing at atomic resolution the interaction between forming and actin filaments. This breakthrough, detailed in the journal Science, not only advances our comprehension of forming function but also offers insights into how mutations in forming genes can precipitate neurological, immune, and cardiovascular disorders.
Previous structural studies hinted at forming adopting a ring-like configuration, encircling the actin filament and moving along with its elongation. However, these insights lacked clarity due to the absence of high-resolution structures depicting forming bound to their active sites on actin filament ends.
The MPI researchers overcame this challenge by meticulously analyzing three distinct forming from fungi, mice, and humans, each exhibiting vastly different actin filament elongation rates. By optimizing experimental conditions, they obtained a wealth of structural data elucidating the intricate interaction between forming and actin filaments.
The newly unveiled structures unveil a paradigm-shifting revelation: forming encircle actin in an asymmetric ring configuration, with one half firmly bound to the filament while the other half remains loosely associated, ready to capture new actin subunits. Upon incorporation of a new actin molecule, the forming arrangement undergoes a dynamic shift, enabling the stable half to engage with the incoming subunit while the other half stabilizes.
This concerted mechanism ensures prolonged association of forming with the growing actin filament end. Contrary to previous assumptions, the structures reveal striking similarities among the three analyzed forming, with only three binding domains actively engaging with actin at any given time.
Furthermore, by introducing specific mutations into forming, the researchers deciphered the factors influencing the varying speeds of actin-forming complexes. Tighter binding between the forming ring and actin filament end impedes the transition to a new actin subunit, resulting in slower filament growth.
These findings not only deepen our understanding of forming-mediated actin dynamics but also pave the way for elucidating the precise functions of the numerous human forming gat the cellular level. Such insights hold promise for unraveling the mechanisms underlying severe diseases associated with forming gene mutations, offering a beacon of hope for therapeutic interventions.

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