Arp2/3-mediated bidirectional actin assembly by SPIN90 dimers in metazoans
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Abstract
Branched actin networks nucleated by the Arp2/3 complex play critical roles in various cellular processes, from cell migration to intracellular transport. However, when activated by WISH/DIP/SPIN90 family proteins, Arp2/3 nucleates linear actin filaments. Unexpectedly, we found that human SPIN90 is a dimer that can nucleate bidirectional actin filaments. To understand the basis for this, we determined a 3 Å resolution structure of human SPIN90-Arp2/3 complex nucleating actin filaments. Our structure shows that SPIN90 dimerises via a 3-helix bundle and interacts with two Arp2/3 complexes. Each SPIN90 molecule binds both Arp2/3 complexes to promote their activation. Our analysis demonstrates that single filament nucleation by Arp2/3 is mechanistically more like branch formation than previously appreciated. The dimerisation domain in SPIN90 orthologues is conserved in metazoans, suggesting that this mode of bidirectional nucleation is a common strategy to generate anti-parallel actin filaments.
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This is a neat paper with impressive work! I'm curious about the dimerization claims though. Throughout the paper, you discuss "SPIN90 dimers," but all experiments use the SPIN90-C truncation (residues 274-722). Have you determined whether full-length SPIN90 also dimerizes?
The N-terminal domains could potentially prevent dimerization in vivo- perhaps by preventing it until binding partners are present, or through intramolecular interactions that affect the dimerization interface.
Your bidirectional actin nucleation model is very compelling, but some experiments with the full-length protein would significantly strengthen the biological implications of this interesting discovery. Although, I'm not sure if full-length SPIN90 purification is feasible.
Thanks again for sharing this great work!!!
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