CNTNAP2 is targeted to endosomes by the polarity protein Par3

Abstract

A decade of genetic studies has established Contactin-associated protein-like 2 (CNTNAP2 ) as a prominent susceptibility gene associated with multiple neurodevelopmental disorders. The development and characterization of Cntnap2 knockout models in multiple species have bolstered this claim by establishing clear connections with certain endophenotypes. Despite these remarkable in vivo findings, CNTNAP2's molecular functions are relatively unexplored, highlighting the need to identify novel protein partners. Here, we characterized an interaction between CNTNAP2 and Partitioning-defective 3 (Par3) -a polarity molecule we isolated in a yeast-two hybrid screen with CNTNAP2's Cterminus. We provide evidence that the two proteins interact via PDZ domainmediated binding, that CNTNAP2 + /Par3 + complexes are largely associated with clathrin-coated endocytic vesicles, and that Par3 causes an enlargement of these structures. Live imaging and fluorescence recovery after photobleaching (FRAP) reveals that Par3 limits the mobility of CNTNAP2 at endosomes, thus stabilizing it at that location. Finally, expression of Par3 but not Par3∆PDZ can cluster endogenous CNTNAP2 in primary neurons. Collectively, we conclude * Corresponding author 1 Equal contribution

The role of selected postsynaptic scaffolding proteins at glutamatergic synapses in autism-related animal models

“…Other findings include alterations in sensory processing, increased avoidance to sounds of moderate intensity, deficit of rapid audiovisual temporal recalibration and exaggerated acoustic startle responses. Gao et al [78] characterized an interaction between CNTNAP2 and the Partitioning-defective 3 protein (PAR3). These authors demonstrated that the two proteins interact through PDZ-mediated binding, since CNTNAP2 + /PAR3 + complexes are largely associated with clathrin-coated endocyte vesicles in heterologous cells.…”