Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle

Laiman, J.; Loh, J.; Tang, W.-C.; Chuang, M.-C.; Liu, H.-K.; Chen, B.-C.; Chang, Y.-C.; Chuang, L.-M.; Liu, Y.-W.

doi:10.1101/2021.10.11.463889

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bioRxiv · 10.1101/2021.10.11.463889

Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle

Laiman, J.·Loh, J.·Tang, W.-C.·Chuang, M.-C.·Liu, H.-K.·Chen, B.-C.·Chang, Y.-C.·Chuang, L.-M.·Liu, Y.-W.

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Abstract

Tight regulation of endocytosis ensures accurate control of cellular signaling and membrane dynamics, which are crucial for tissue morphogenesis and functions. Mutations of Bin1 and dynamin-2 (Dyn2), proteins that generate membrane curvature and sever endocytic invaginations, respectively, cause progressive hereditary myopathy. Here, we show that Bin1 inhibits Dyn2 via direct interaction of its SRC Homology 3 (SH3) domain with the proline-rich domain (PRD) of Dyn2. Phosphorylation of S848 of Dyn2 by GSK3, a kinase downstream of insulin signaling, relieves Dyn2 from the inhibition of Bin1 and promotes endocytosis in muscle. Mutations of Bin1 associated with centronuclear myopathy disrupt its inhibition of Dyn2, thereby exaggerating Dyn2 fission activity and causing excessive fragmentation of T-tubules in the muscle cells. Our work reveals how Bin1-Dyn2 interaction fine-tunes membrane remodeling at the molecular level, and lay the foundation for future exploration of endocytic regulation and hereditary muscle diseases.

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Laiman, J., Loh, J., Tang, W.-C., Chuang, M.-C., Liu, H.-K., Chen, B.-C., Chang, Y.-C., Chuang, L.-M., Liu, Y.-W.. 2021-10-11. Dynamin-2 Phosphorylation as A Critical Regulatory Target of Bin1 and GSK3α for Endocytosis in Muscle. https://doi.org/10.1101/2021.10.11.463889

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