Phase separation and zinc-induced transition modulate synaptic distribution and association of autism-linked CTTNBP2 and SHANK3

Pu-Yun Shih, Yu-Lun Fang, Sahana Shankar, Sue-Ping Lee, Hsiao-Tang Hu, Hsin Chen, Ting-Fang Wang, Kuo-Chiang Hsia () and Yi-Ping Hsueh ()
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Pu-Yun Shih: Academia Sinica
Yu-Lun Fang: Academia Sinica
Sahana Shankar: Academia Sinica
Sue-Ping Lee: Academia Sinica
Hsiao-Tang Hu: Academia Sinica
Hsin Chen: Academia Sinica
Ting-Fang Wang: Academia Sinica
Kuo-Chiang Hsia: Academia Sinica
Yi-Ping Hsueh: Academia Sinica

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Many synaptic proteins form biological condensates via liquid-liquid phase separation (LLPS). Synaptopathy, a key feature of autism spectrum disorders (ASD), is likely relevant to the impaired phase separation and/or transition of ASD-linked synaptic proteins. Here, we report that LLPS and zinc-induced liquid-to-gel phase transition regulate the synaptic distribution and protein-protein interaction of cortactin-binding protein 2 (CTTNBP2), an ASD-linked protein. CTTNBP2 forms self-assembled condensates through its C-terminal intrinsically disordered region and facilitates SHANK3 co-condensation at dendritic spines. Zinc binds the N-terminal coiled-coil region of CTTNBP2, promoting higher-order assemblies. Consequently, it leads to reduce CTTNBP2 mobility and enhance the stability and synaptic retention of CTTNBP2 condensates. Moreover, ASD-linked mutations alter condensate formation and synaptic retention of CTTNBP2 and impair mouse social behaviors, which are all ameliorated by zinc supplementation. Our study suggests the relevance of condensate formation and zinc-induced phase transition to the synaptic distribution and function of ASD-linked proteins.

Date: 2022
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DOI: 10.1038/s41467-022-30353-0

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