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- Title
Mechanism of synergistic activation of Arp2/3 complex by cortactin and WASP-family proteins.
- Authors
Fregoso, Fred E.; Boczkowska, Malgorzata; Rebowski, Grzegorz; Carman, Peter J.; van Eeuwen, Trevor; Dominguez, Roberto
- 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 understood how cortactin performs these functions. We describe the 2.89 Å resolution cryo-EM structure of cortactin's N-terminal domain (Cort1-76) 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. Arp2/3 complex is activated by nucleation promoting factors (NPFs) to form actin branches that are stabilized by cortactin. Here, the authors show that NPFs and cortactin activate Arp2/3 complex synergistically by helping recruit the complex to F-actin and by stabilizing its active conformation
- Subjects
F-actin; PROTEINS; ACTIN; DIMERIZATION; NUCLEATION
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-42229-y