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bioRxiv · 10.1101/2023.03.15.532613

Regulation of FMRP granule structure and function through phosphorylation

Kharod, S. C.·Hwang, D.·Castillo, P. E.·Yoon, Y. J.
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Abstract

Fragile X messenger ribonucleoprotein (FMRP) is an RNA-binding protein implicated in autism that suppresses translation and forms granules. While FMRP function has been well-studied, how phosphorylation regulates granule binding and function remains limited. Here, we found that Fragile X patient-derived I304N mutant FMRP could not stably bind granules, underscoring the essential nature of FMRP granule association for function. Next, phosphorylation on serine 499 (S499) led to differences in puncta size, intensity, contrast, and transport as shown by phospho-deficient (S499A) and phospho-mimic (S499D) mutant FMRP granules. Additionally, S499D exchanged slowly on granules relative to S499A, suggesting that phosphorylated FMRP can attenuate translation. Furthermore, the S499A mutant enhanced translation in presynaptic boutons of the mouse hippocampus. Thus, the phospho-state of FMRP altered the structure of individual granules with changes in transport and translation to achieve spatiotemporal regulation of local protein synthesis. TeaserThe phosphorylation-state of S499 on FMRP can change FMRP granule structure and function to facilitate processive transport or local protein synthesis.

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Kharod, S. C., Hwang, D., Castillo, P. E., Yoon, Y. J.. 2023-03-15. Regulation of FMRP granule structure and function through phosphorylation. https://doi.org/10.1101/2023.03.15.532613

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