CNTNAP2 is targeted to endosomes by the polarity protein PAR3

Ruoqi Gao, Christopher P. Pratt, Sehyoun Yoon, Maria Dolores Martin-de-Saavedra, Marc P. Forrest, Peter Penzes*

*Corresponding author for this work

Research output: Contribution to journalArticle

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 isolated in a yeast two-hybrid screen with CNTNAP2’s C-terminus. We provide evidence that the two proteins interact via PDZ domain-mediated binding, that CNTNAP2+/PAR3+ complexes are largely associated with clathrin-coated endocytic vesicles in heterologous cells and that PAR3 causes an enlargement of CNTNAP2 puncta size. Live imaging and fluorescence recovery after photobleaching (FRAP) reveals that PAR3 limits the mobility of CNTNAP2. Finally, overexpression of PAR3 but not a PAR3 mutant lacking all PDZ domains (PAR3∆PDZall) can cluster endogenous CNTNAP2 in primary neurons. Collectively, we conclude that PAR3 regulates CNTNAP2 spatial localization.

Original languageEnglish (US)
Pages (from-to)1074-1086
Number of pages13
JournalEuropean Journal of Neuroscience
Volume51
Issue number4
DOIs
StatePublished - Feb 1 2020

Keywords

  • Cos7 cells
  • interneurons
  • protein-protein interactions
  • trafficking

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'CNTNAP2 is targeted to endosomes by the polarity protein PAR3'. Together they form a unique fingerprint.

  • Cite this

    Gao, R., Pratt, C. P., Yoon, S., Martin-de-Saavedra, M. D., Forrest, M. P., & Penzes, P. (2020). CNTNAP2 is targeted to endosomes by the polarity protein PAR3. European Journal of Neuroscience, 51(4), 1074-1086. https://doi.org/10.1111/ejn.14620