Abstract
Formins play an important role in the polymerization of unbranched actin filaments, and particular formins slow elongation by 5-95%. We studied the interactions between actin and the FH2 domains of formins Cdc12, Bni1 and mDia1 to understand the factors underlying their different rates of polymerization. All-atom molecular dynamics simulations revealed two factors that influence actin filament elongation and correlate with the rates of elongation. First, FH2 domains can sterically block the addition of new actin subunits. Second, FH2 domains flatten the helical twist of the terminal actin subunits, making the end less favorable for subunit addition. Coarse-grained simulations over longer time scales support these conclusions. The simulations show that filaments spend time in states that either allow or block elongation. The rate of elongation is a time-average of the degree to which the formin compromises subunit addition rather than the formin-actin complex literally being in 'open' or 'closed' states.
Highlights
Actin is one of the most abundant proteins in eukaryotic cells and is important for numerous functions regulated by interactions with many other proteins (Pollard and Cooper, 2009; Dominguez and Holmes, 2011; Blanchoin et al, 2014)
A 3.4 Acrystal structure of a dimer of FMNL3 formin homology 2 (FH2) domains bound to actin has contacts between the FMNL3 FH2 domain and actin similar to those of the Bni1-FH2 domains (Thompson et al, 2013). This structure has a two-fold axis of symmetry between physically separated actin subunits, so it is less informative regarding the structure of FH2 domains bound to a helical actin filament than the Bni1FH2-actin structure, upon which Baker et al (2015) and we based our models for molecular dynamics (MD) simulations
We used computational modeling to investigate how formin FH2 domains interact with the barbed ends of actin filaments
Summary
Actin is one of the most abundant proteins in eukaryotic cells and is important for numerous functions regulated by interactions with many other proteins (Pollard and Cooper, 2009; Dominguez and Holmes, 2011; Blanchoin et al, 2014). The dynamic actin network in the cell cortex enables cells to maintain specific shapes in addition to supporting the plasma membrane. Actin filaments in lamellipodia drive cellular movements, and contractile rings of actin filaments are responsible for cytokinesis (Chesarone et al, 2010). Transitions of actin between monomeric and filamentous states is a key feature of these dynamic systems (Pollard and Cooper, 2009). Formins regulate actin assembly by nucleating and directing the elongation of unbranched actin filaments (Grikscheit and Grosse, 2016). Formin malfunctions are associated with cancer (Favaro et al, 2006; Favaro et al, 2003; Lizarraga et al, 2009; Sahai and Marshall, 2002) and immune disorders (Colucci-Guyon et al, 2005), so characterizing formins is crucial for understanding these important diseases
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
