Abstract
Profilin is one of the most abundant and central actin regulatory proteins in eukaryotic cells. Profilin also
decorates the sides of microtubules and indirectly influences cellular microtubule dynamics through
interactions with Formins. Here, we investigated whether Profilin has direct regulatory effects on
microtubule dynamics. We show that human Profilin‐1 binds to microtubules in vitro and enhances the
growth rate of microtubules several‐fold. These microtubule effects are conserved in budding yeast and
Drosophila Profilin homologs, and are unaffected by mutations in its canonical actin monomer– or poly‐
L‐proline–binding sites. Instead, microtubule regulation depends on several residues mutated in patients
with amyotrophic lateral sclerosis (ALS). The enhanced microtubule dynamics elicited by Profilin are
attenuated by increasing concentrations of actin monomers. This suggests a competitive relationship
between microtubules and actin for Profilin binding and this agrees with the close proximity of the
known actin and microtubule binding surfaces. Consistent with these biochemical results, a two‐fold
increase in expression of wildtype Profilin accelerates the growth rate of microtubules in cells, and cells
expressing similar levels of each of the ALS‐associated Profilin mutants did not. These results
demonstrate Profilin directly interacts with and enhances the growth rate of microtubules in vitro and in
cells, and indicate that Profilin coordinates cellular actin and microtubule dynamics. Further, cells
harboring ALS‐linked Profilin mutations may ultimately leads to the motor neuron degeneration through
defective microtubule regulation.
decorates the sides of microtubules and indirectly influences cellular microtubule dynamics through
interactions with Formins. Here, we investigated whether Profilin has direct regulatory effects on
microtubule dynamics. We show that human Profilin‐1 binds to microtubules in vitro and enhances the
growth rate of microtubules several‐fold. These microtubule effects are conserved in budding yeast and
Drosophila Profilin homologs, and are unaffected by mutations in its canonical actin monomer– or poly‐
L‐proline–binding sites. Instead, microtubule regulation depends on several residues mutated in patients
with amyotrophic lateral sclerosis (ALS). The enhanced microtubule dynamics elicited by Profilin are
attenuated by increasing concentrations of actin monomers. This suggests a competitive relationship
between microtubules and actin for Profilin binding and this agrees with the close proximity of the
known actin and microtubule binding surfaces. Consistent with these biochemical results, a two‐fold
increase in expression of wildtype Profilin accelerates the growth rate of microtubules in cells, and cells
expressing similar levels of each of the ALS‐associated Profilin mutants did not. These results
demonstrate Profilin directly interacts with and enhances the growth rate of microtubules in vitro and in
cells, and indicate that Profilin coordinates cellular actin and microtubule dynamics. Further, cells
harboring ALS‐linked Profilin mutations may ultimately leads to the motor neuron degeneration through
defective microtubule regulation.
| Original language | English |
|---|---|
| Pages (from-to) | 1138 |
| Journal | Molecular Biology of the Cell |
| Volume | 28 |
| Publication status | Published - 2017 |
| Event | 2017 Annual Joint Meeting of the American Society for Cell Biology and the European Molecular Biology Organization - Philadelphia, United States Duration: 2 Dec 2017 → 6 Dec 2017 |