Competition for delivery of profilin-actin to barbed ends limits the rate of formin-mediated actin filament elongation

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Formins direct the elongation of unbranched actin filaments by binding their barbed ends and processively stepping onto incoming actin monomers to incorporate them into the filament. Binding of profilin to actin monomers creates profilin-actin complexes, which then bind polyproline tracts located in formin homology 1 (FH1) domains. Diffusion of these natively disordered domains enables direct delivery of profilin-actin to the barbed end, speeding the rate of filament elongation. In this study, we investigated the mechanism of coordinated actin delivery from the multiple polyproline tracts in formin FH1 domains. We found that each polyproline tract can efficiently mediate polymerization, but that all tracts do not generate the same rate of elongation. In WT FH1 domains, the multiple polyproline tracts compete to deliver profilin-actin to the barbed end. This competition ultimately limits the rate of formin-mediated elongation. We propose that intrinsic properties of the filament-binding FH2 domain tune the efficiency of FH1-mediated elongation by directly regulating the rate of monomer incorporation at the barbed end. A strong correlation between competitive FH1-mediated profilin-actin delivery and FH2-regulated gating of the barbed end effectively limits the elongation rate, thereby obviating the need for evolutionary optimization of FH1 domain sequences.

Original languageEnglish (US)
Pages (from-to)4513-4525
Number of pages13
JournalJournal of Biological Chemistry
Issue number14
StatePublished - Apr 3 2020

Bibliographical note

Funding Information:
This work was supported by National Institutes of Health Research Grant GM122787 (to N. C.) and National Institutes of Health Training Grant AR007612 (to M. E. Z.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the respon-sibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2020 Zweifel and Courtemanche. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.


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