PIST couples actin cytoskeleton dynamics through a WH2-like actin-binding domain.

Purkinje cell synapses in the cerebellar cortex require tight coordination between receptor trafficking and cytoskeletal remodeling to sustain synaptogenesis, structural plasticity, and motor learning. The glutamate δ2 receptor (GluRδ2), a hallmark component of parallel fiber-Purkinje cell synapses, depends on intracellular scaffolding proteins for proper localization and signaling. PIST (GOPC), a neuronal PDZ domain-containing protein originally identified as a selective GluRδ2-interacting partner, has emerged as an important regulator of receptor trafficking and synaptic organization. Here, we reveal a previously unrecognized biochemical function of PIST as an actin-binding protein. Biochemical and cellular analyses show that PIST directly associates with filamentous actin in a concentration-dependent manner, suppresses actin polymerization in vitro, and co-localizes with actin in neuronal cells. Mechanistically, this interaction is mediated by a WH2-like motif within PIST. PIST may function as a molecular link between the actin cytoskeleton and the protein trafficking machinery, suggesting a potential new mechanism underlying the coordinated regulation of receptor transport and synaptic structural plasticity in neurons.