A cooperative jack model of random coil‐to‐elongation transition of the FH1 domain by profilin binding explains formin motor behavior in actin polymerization

Abstract

a b s t r a c tFilopodia are essential for the development of neuronal growth cones, cell polarity and cell migration. Their protrusions are powered by the polymerization of actin filaments linked to the plasma membrane, catalyzed by formin proteins. The acceleration of polymerization depends on the number of profilin-actins binding with the formin-FH1 domain. Biophysical characterization of the disordered formin-FH1 domain remains a challenge. We analyzed the conformational distribution of the diaphanous-related formin mDia1-FH1 bound with one to six profilins. We found a coil-to-elongation transition in the FH1 domain. We propose a cooperative ''jack'' model for the Formin-Homology-1 (FH1) domain of formins stacked by profilin-actins.

Computational modeling highlights the role of the disordered Formin Homology 1 domain in profilin‐actin transfer

“…We also note that the model of mDia1‐FH1(6PRM) structure by Zhao et al . predicted a similar R g compared to our all‐atom simulations (‘ZLHL’ in Fig. ).…”

“…The dependence of R g on profilin occupancy for our models is slightly weaker than previously predicted by ZLHL (Fig. ).…”

“…(A, B): Cumulative distribution of radius of gyration of mD ia1‐ FH 1(6 PRM ) and Cdc12‐ FH 1 in AA serial and PTWTE simulations. (C) Comparison of M&F‐K empirical prediction of IDP hydrodynamic radius to radius of gyration in AA serial, AA PTWTE , coarse‐grained simulations using the KH and KH RP models, and the ZLHL radius of gyration calculation for mD ia1 .…”

“…For these snapshots the FH 1 R g and distance between each pair occupying profilin(‐actin)s is within the FWHM of their respective distributions. (B) Fold increase in mD ia1‐ FH 1(6 PRM ) R g from respective unoccupied R g predictions for the KH RP and KH RP ‐ WCA models, as described in the main text, and comparison to ZLHL prediction . Labels P and PA indicate profilin or profilin‐actin occupancy.…”

Cell Biology: Capturing Formin’s Mechano-Inhibition

“…A more detailed analysis may be needed to account for the effect of multiple active profilin-binding sites. Various additional factors may play a non-trivial role in actin filament polymerization, such as: differential rates of profilin binding to different sites in the FH1 domain as well as differential rates of transfer of profilin–actin to either actin protofilament as proposed by Courtemanche and Pollard [10]; cooperative effects by multiple profilins as proposed by Zhao et al [18]; and/or (transient) binding of FH1 domains to FH2 domains as suggested by Jégou et al [15]. A complication to note regarding prior experiments is that it has been difficult to demonstrate whether force is exerted equally on both FH1 domains of the formin dimer.…”