Structural basis for polarized elongation of actin filaments

Zsolnay, Vilmos; Katkar, Harshwardhan H.; Chou, Steven Z.; Pollard, Thomas D.; Voth, Gregory A.

doi:10.1073/pnas.2011128117

Cited by 35 publications

(47 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In simulations the terminal subunits of filaments tend toward conformations resembling G-actin. This behavior leads to opposite effects at the two filament ends with different sets of unique contacts at each location, which produce different kinetics of monomer addition 13 .…”

Section: Introductionmentioning

confidence: 99%

Bound nucleotide can control the dynamic architecture of monomeric actin

Ali

Zahm

Rosen

2022

Nat Struct Mol Biol

View full text Add to dashboard Cite

Polymerization of actin into cytoskeletal filaments is coupled to its bound adenine nucleotides. The mechanism by which nucleotide modulates actin functions has not been evident from analyses of ATP- and ADP-bound crystal structures of the actin monomer. We report that NMR chemical shift differences between the two forms are globally distributed. Furthermore, microsecond–millisecond motions are spread throughout the molecule in the ATP form, but largely confined to subdomains 1 and 2, and the nucleotide binding site in the ADP form. Through these motions, the ATP- and ADP-bound forms sample different high-energy conformations. A deafness-causing, fast-nucleating actin mutant populates the high-energy conformer of ATP-actin more than the wild-type protein, suggesting that this conformer may be on the pathway to nucleation. Together, the data suggest a model in which differential sampling of a nucleation-compatible form of the actin monomer may contribute to control of actin filament dynamics by nucleotide.

show abstract

Section: Introductionmentioning

confidence: 99%

Bound nucleotide can control the dynamic architecture of monomeric actin

Ali

Zahm

Rosen

2022

Nat Struct Mol Biol

View full text Add to dashboard Cite

show abstract

“…Another option is that the repetitive hydrophobic sequence in the tip of the D-loop has an impact on the overall dynamics of the D-loop. Earlier biochemical 50 – 52 , and MD simulation 53 studies provided evidence that the D-loop samples various conformations in the filament. Some conformations may be more favorable for the association of the D-loop with the adjacent subunit, and these states can be affected by the D-loop primary sequence.…”

Section: Resultsmentioning

confidence: 99%

Structural basis of rapid actin dynamics in the evolutionarily divergent Leishmania parasite

et al. 2022

View full text Add to dashboard Cite

Actin polymerization generates forces for cellular processes throughout the eukaryotic kingdom, but our understanding of the ‘ancient’ actin turnover machineries is limited. We show that, despite > 1 billion years of evolution, pathogenic Leishmania major parasite and mammalian actins share the same overall fold and co-polymerize with each other. Interestingly, Leishmania harbors a simple actin-regulatory machinery that lacks cofilin ‘cofactors’, which accelerate filament disassembly in higher eukaryotes. By applying single-filament biochemistry we discovered that, compared to mammalian proteins, Leishmania actin filaments depolymerize more rapidly from both ends, and are severed > 100-fold more efficiently by cofilin. Our high-resolution cryo-EM structures of Leishmania ADP-, ADP-Pi- and cofilin-actin filaments identify specific features at actin subunit interfaces and cofilin-actin interactions that explain the unusually rapid dynamics of parasite actin filaments. Our findings reveal how divergent parasites achieve rapid actin dynamics using a remarkably simple set of actin-binding proteins, and elucidate evolution of the actin cytoskeleton.

show abstract

“…Recently, all-atom level MD simulations were conducted to investigate the molecular mechanism of the polarized elongation of actin filament [23,62]. Such all-atom level simulations enable explicit description of the effect of nucleotide state on the actin conformations at the two ends of the filament.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular dynamics (MD) simulations have shown great success in the studies of structural dynamics of actin filament due to the unprecedented spatial and temporal resolutions [23][24][25][26][27]. However, the molecular events involved in the filament growth typically occur at the time scales longer than millisecond, which are far beyond the capability of conventional all-atom MD simulations.…”

Section: Introductionmentioning

confidence: 99%

Allostery and molecular stripping mechanism in profilin regulated actin filament growth

Zhang

Cao

et al. 2021

New J. Phys.

View full text Add to dashboard Cite

Profilin is an actin-sequestering protein and plays key role in regulating the polarized growth of actin filament. Binding of profilin to monomeric actin (G-actin) allows continuous elongation at the barbed end, but not the pointed end, of filament. How G-actin exchanges between the profilin-sequestered state and the filament state (F-actin) to support the barbed end elongation is not well understood. Here, we investigate the involved molecular mechanism by constructing a multi-basin energy landscape model and performing molecular simulations. We showed that the actin exchanging occurs by forming a ternary complex. The interactions arising from the barbed end binding drive the conformational change of the attached G-actin in the ternary complex from twist conformation to more flatten conformation without involving the change of nucleotide state, which in turn destabilizes the actin-profilin interface and promotes the profilin stripping event through allosteric coupling. We also showed that attachment of free profilin to the barbed end induces conformational change of the barbed end actin and facilitates its stripping from the filament. These results suggest a molecular stripping mechanism of the polarized actin filament growth dynamics controlled by the concentrations of the actin-profilin dimer and the free profilin, in which the allosteric feature of the monomeric actin plays crucial role.

show abstract

Structural basis for polarized elongation of actin filaments

Cited by 35 publications

References 28 publications

Bound nucleotide can control the dynamic architecture of monomeric actin

Bound nucleotide can control the dynamic architecture of monomeric actin

Structural basis of rapid actin dynamics in the evolutionarily divergent Leishmania parasite

Allostery and molecular stripping mechanism in profilin regulated actin filament growth

Contact Info

Product

Resources

About