title: FMRP regulates miR196a-mediated repression of HOXB8 via interaction with the AGO2 MID domain.
abstract: Fragile X syndrome (FXS) is caused by the loss of expression of fragile X mental retardation protein (FMRP), a selective RNA-binding protein that negatively regulates mRNA substrates. FMRP can regulate the translation via the cross-talk with the miRNA machinery, but the functional association among FMRP, miRNAs and mutual target mRNAs has rarely been studied. In this research, we find that HOXB8 mRNA is a target of FMRP associated with miR-196a-induced silencing, and discover that phosphorylation of FMRP promotes the miR-196a-mediated repression of HOXB8 without affecting the interaction between FMRP and mRNA. We further identify that the FMRP-binding site involved in the miR-196a-mediated repression of HOXB8 locates in the downstream neighbourhood of the miR-196a recognition element in the 3'UTR of HOXB8. Importantly, we reveal that FMRP faces toward the MID domain of AGO2 and interacts with a specific binding pocket (coordination with T544, K533 and K570) in the domain. Our research might provide new insights into both the cross-talk between FMRP and miRNA-mediated regulation of mRNA translation and the molecular pathogenesis of FXS.
authors.affiliation: Single-Molecule Detection and Imaging Laboratory, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Guangdong, China. zhangcy@siat.ac.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Li
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Li-rong
authors.initials: LR
authors.lastname: Zhang
authors.forename: Chun-yang
authors.initials: CY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D060565:Argonaute Proteins / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D008958:Models, Molecular; D010766:Phosphorylation; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D060565:Argonaute Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D018398:Homeodomain Proteins; D035683:MicroRNAs; D012333:RNA, Messenger; C466422:AGO2 protein, human; C497683:FMR1 protein, human; C490669:HOXB8 protein, human; C542543:MIRN196 microRNA, human