Evolutionarily convergent mechanism of formin regulation coordinates actin polymerization in apicomplexan parasites.

Abstract

Apicomplexan parasites rely on actin-based motility for host cell invasion and for their dissemination. Although previous studies implicate formin 1 (FRM1) in governing this process in <i>Toxoplasma</i>, the mechanisms that position it at the cell apex and regulate its activity during the transition from intracellular replication to active motility remain unclear. Here, we demonstrate that FRM1 is complexed with a protein methyl transferase that stabilizes it from degradation and positions it at the cell apex. Moreover, we identify a conserved intramolecular interaction within FRM1 that serves as a critical regulatory switch that is functionally conserved in <i>Plasmodium</i> and other apicomplexan parasites. Using structural modeling combined with biochemical assays, we define two regulatory elements located upstream of the FH2 domain that mediate autoinhibition. Repositioning these elements by activation of an intramolecular switch relieves autoinhibition and activates actin polymerization by the FH2 domain. Collectively, these findings elucidate how precise regulation of FRM1 coordinates actin polymerization, parasite motility and host cell invasion.