Structural Basis of Arp2/3 Complex Inhibition by GMF, Coronin, and Arpin

Olga Sokolova (1) , Angelina Chemeris (2, 1) , Siyang Guo (3) , Salvatore L Alioto (3) , Meghal Gandhi (3) , Shae Padrick (4) , Evgeniya Pechnikova (5) , Violaine David (2) , Alexis Gautreau (2) , Bruce Goode (3)

1 Lomonosov Moscow State University, Biological Faculty
2 BIOC - Laboratoire de Biochimie de l'Ecole polytechnique
3 Brandeis University
4 DBMB - Department of Biochemistry and Molecular Biology
5 Shubnikov Institute of Crystallography

The evolutionarily conserved Arp2/3 complex plays a central role in nucleating the branched actin filament arrays that drive cell migration, endocytosis, and other processes. To better understand Arp2/3 complex regulation, we used single particle electron microscopy to compare the structures of Arp2/3 complex bound to three different inhibitory ligands: GMF, Coronin, and Arpin. Although the three inhibitors have distinct binding sites on Arp2/3 complex, they each induced an ‘open’ nucleation-inactive conformation. Coronin promoted a standard (previously described) open conformation of Arp2/3 complex, with the N-terminal β-propeller domain of Coronin positioned near the p35/ARPC2 subunit of Arp2/3 complex. GMF induced two distinct open conformations of Arp2/3 complex, which correlated with two suggested binding sites for GMF. Further, GMF synergized with Coronin in inhibiting actin nucleation by Arp2/3 complex. Arpin, which uses VCA-related acidic (A) motifs to interact with the Arp2/3 complex, induced the standard open conformation, and two new masses appeared at positions near Arp2 and Arp3. Further, Arpin showed additive inhibitory effects on Arp2/3 complex with Coronin and GMF. Together, these data suggest that Arp2/3 complex conformation is highly polymorphic and that its activities can be controlled combinatorially by different inhibitory ligands.

Keywords: Actin nucleation; Single particle EM; Yeast; Conformation

Domains: Molecular biology; Cellular Biology; Quantitative Methods [q-bio.QM]; Cancer

Olga Sokolova, Angelina Chemeris, Siyang Guo, Salvatore L Alioto, Meghal Gandhi, et al.. Structural Basis of Arp2/3 Complex Inhibition by GMF, Coronin, and Arpin. Journal of Molecular Biology, 2017, 429 (2), pp.237-248. ⟨10.1016/j.jmb.2016.11.030⟩. ⟨hal-01964479⟩