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Biochemical characterization of actin assembly mechanisms with ALS-associated profilin variants

View ORCID ProfileXinbei Liu, View ORCID ProfileMorgan L. Pimm, View ORCID ProfileBrian Haarer, View ORCID ProfileAndrew T. Brawner, View ORCID ProfileJessica L. Henty-Ridilla
doi: https://doi.org/10.1101/2022.01.05.475096
Xinbei Liu
aDepartment of Biochemistry & Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210
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Morgan L. Pimm
aDepartment of Biochemistry & Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210
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Brian Haarer
aDepartment of Biochemistry & Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210
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Andrew T. Brawner
bDepartment of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY, 13210
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Jessica L. Henty-Ridilla
aDepartment of Biochemistry & Molecular Biology, SUNY Upstate Medical University, Syracuse, NY, 13210
bDepartment of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, NY, 13210
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  • For correspondence: ridillaj@upstate.edu
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Abstract

Eight separate mutations in the actin-binding protein profilin-1 have been identified as a rare cause of amyotrophic lateral sclerosis (ALS). Profilin is essential for many neuronal cell processes through its regulation of lipids, nuclear signals, and cytoskeletal dynamics, including actin filament assembly. Direct interactions between profilin and actin monomers inhibit actin filament polymerization. In contrast, profilin can also stimulate polymerization by simultaneously binding actin monomers and proline-rich tracts found in other proteins. Whether the ALS-associated mutations in profilin compromise these actin assembly functions is unclear. We performed a quantitative biochemical comparison of the direct and formin-mediated impact for the eight ALS-associated profilin variants on actin assembly using classic protein-binding and single-filament microscopy assays. We determined that the binding constant of each profilin for actin monomers generally correlates with the actin nucleation strength associated with each ALS-related profilin. In the presence of formin, the A20T, R136W, Q139L, and C71G variants failed to activate the elongation phase of actin assembly. This diverse range of formin-activities is not fully explained through profilin-PLP interactions, as all ALS-associated variants bind a formin-derived PLP peptide with similar affinities. However, chemical denaturation experiments suggest that the folding stability of these profilins impact some of these effects on actin assembly. Thus, changes in profilin protein stability and alterations in actin filament polymerization may both contribute to the profilin-mediated actin disruptions in ALS.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • A negative control is now included in Figure 5. A new summary figure is now included. Minor edits to figures and text were made for clarity.

  • https://doi.org/10.5281/zenodo.5975762

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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Posted February 11, 2022.
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Biochemical characterization of actin assembly mechanisms with ALS-associated profilin variants
Xinbei Liu, Morgan L. Pimm, Brian Haarer, Andrew T. Brawner, Jessica L. Henty-Ridilla
bioRxiv 2022.01.05.475096; doi: https://doi.org/10.1101/2022.01.05.475096
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Biochemical characterization of actin assembly mechanisms with ALS-associated profilin variants
Xinbei Liu, Morgan L. Pimm, Brian Haarer, Andrew T. Brawner, Jessica L. Henty-Ridilla
bioRxiv 2022.01.05.475096; doi: https://doi.org/10.1101/2022.01.05.475096

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