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Curr Biol. 2017 Nov 20;27(22):3535-3543.e4. doi: 10.1016/j.cub.2017.10.002. Epub 2017 Nov 9.

Profilin Directly Promotes Microtubule Growth through Residues Mutated in Amyotrophic Lateral Sclerosis.

Author information

1
Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454, USA.
2
Department of Biology, Brandeis University, 415 South Street, Waltham, MA 02454, USA. Electronic address: goode@brandeis.edu.

Abstract

Profilin is an abundant actin monomer-binding protein with critical actin regulatory roles in vivo [1, 2]. However, profilin also influences microtubule dynamics in cells, which may be mediated in part through its interactions with formins that in turn bind microtubules [3, 4]. Specific residues on human profilin-1 (PFN1) are mutated in patients with amyotrophic lateral sclerosis (ALS) [5, 6]. However, the observation that some ALS-linked PFN1 mutants fail to alter cellular actin organization or dynamics [5-8] or in vitro actin-monomer affinity [9] has been perplexing, given that profilin is best understood as an actin regulator. Here, we investigated direct effects of profilin on microtubule dynamics and whether ALS-linked mutations in PFN1 disrupt such functions. We found that human, fly, and yeast profilin homologs all directly enhance microtubule growth rate by several-fold in vitro. Microtubule stimulatory effects were unaffected by mutations in the canonical actin- or poly-proline-binding sites of profilin. Instead, microtubule activities depended on specific surface residues on profilin mutated in ALS patients. Furthermore, microtubule effects were attenuated by increasing concentrations of actin monomers, suggesting competition between actin and microtubules for binding profilin. Consistent with these biochemical observations, a 2-fold increase in the expression level of wild-type PFN1, but not the ALS-linked PFN1 mutants, increased microtubule growth rates in cells. Together, these results demonstrate that profilin directly enhances the growth rate of microtubules. They further suggest that ALS-linked mutations in PFN1 may perturb cellular microtubule dynamics and/or the coordination between the actin and microtubule cytoskeletons, leading to motor neuron degeneration.

KEYWORDS:

ALS; actin; crosstalk; microtubule; neurodegeneration; profilin; structure; tubulin

PMID:
29129529
PMCID:
PMC5772683
DOI:
10.1016/j.cub.2017.10.002
[Indexed for MEDLINE]
Free PMC Article

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