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Title | Mechanism of synergistic activation of Arp2/3 complex by cortactin and WASP-family proteins. |
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Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 6894, Year 2023 |
Publish date | Oct 28, 2023 |
Authors | Fred E Fregoso / Malgorzata Boczkowska / Grzegorz Rebowski / Peter J Carman / Trevor van Eeuwen / Roberto Dominguez / |
PubMed Abstract | Cortactin coactivates Arp2/3 complex synergistically with WASP-family nucleation-promoting factors (NPFs) and stabilizes branched networks by linking Arp2/3 complex to F-actin. It is poorly ...Cortactin coactivates Arp2/3 complex synergistically with WASP-family nucleation-promoting factors (NPFs) and stabilizes branched networks by linking Arp2/3 complex to F-actin. It is poorly understood how cortactin performs these functions. We describe the 2.89 Å resolution cryo-EM structure of cortactin's N-terminal domain (Cort) bound to Arp2/3 complex. Cortactin binds Arp2/3 complex through an inverted Acidic domain (D20-V29), which targets the same site on Arp3 as the Acidic domain of NPFs but with opposite polarity. Sequences N- and C-terminal to cortactin's Acidic domain do not increase its affinity for Arp2/3 complex but contribute toward coactivation with NPFs. Coactivation further increases with NPF dimerization and for longer cortactin constructs with stronger binding to F-actin. The results suggest that cortactin contributes to Arp2/3 complex coactivation with NPFs in two ways, by helping recruit the complex to F-actin and by stabilizing the short-pitch (active) conformation, which are both byproducts of cortactin's core function in branch stabilization. |
External links | Nat Commun / PubMed:37898612 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.89 Å |
Structure data | EMDB-41135, PDB-8tah: |
Chemicals | ChemComp-MG: ChemComp-ATP: |
Source |
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Keywords | CONTRACTILE PROTEIN / Complex / migration / actin / cytoskeleton |