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eNeuro. 2016 Nov 21;3(6). pii: ENEURO.0092-16.2016. eCollection 2016 Nov-Dec.

Mammalian FMRP S499 Is Phosphorylated by CK2 and Promotes Secondary Phosphorylation of FMRP.

Author information

1
Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; Department of Neurobiology, Yale University School of Medicine, New Haven, CT 06510.
2
Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT 06510.
3
Department of Chemistry and Biochemistry, Duquesne University , Pittsburgh, PA 15282.
4
Departments of Neurosurgery, and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06510; Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha 410008, China.

Abstract

The fragile X mental retardation protein (FMRP) is an mRNA-binding regulator of protein translation that associates with 4-6% of brain transcripts and is central to neurodevelopment. Autism risk genes' transcripts are overrepresented among FMRP-binding mRNAs, and FMRP loss-of-function mutations are responsible for fragile X syndrome, the most common cause of monogenetic autism. It is thought that FMRP-dependent translational repression is governed by the phosphorylation of serine residue 499 (S499). However, recent evidence suggests that S499 phosphorylation is not modulated by metabotropic glutamate receptor class I (mGluR-I) or protein phosphatase 2A (PP2A), two molecules shown to regulate FMRP translational repression. Moreover, the mammalian FMRP S499 kinase remains unknown. We found that casein kinase II (CK2) phosphorylates murine FMRP S499. Further, we show that phosphorylation of FMRP S499 permits phosphorylation of additional, nearby residues. Evidence suggests that these nearby residues are modulated by mGluR-I and PP2A pathways. These data support an alternative phosphodynamic model of FMRP that is harmonious with prior studies and serves as a framework for further investigation.

KEYWORDS:

FMRP; casein kinase; fragile X; mTOR; phosphorylation; translation

PMID:
27957526
PMCID:
PMC5116651
DOI:
10.1523/ENEURO.0092-16.2016
[Indexed for MEDLINE]
Free PMC Article

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