The amino-terminal structure of human fragile X mental retardation protein obtained using precipitant-immobilized imprinted polymers

Hu, Yu‐Feng; Chen, Zhongzhou; Fu, Yan; He, Qile; Jiang, Libin; Zheng, Jianyun; Gao, Yina; Mei, Pinchao; Ren, Xueqin

doi:10.1038/ncomms7634

Cited by 42 publications

(30 citation statements)

References 56 publications

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“…Small-angle X-ray scattering measurements were performed on beamline BL19U2 at the SSRF following previously published methods 54,55 . Briefly, all proteins were subjected to size exclusion chromatography in a buffer containing 20 mM HEPES, pH 7.3, 500 mM NaCl, 2 mM β-mercaptoethanol.…”

Section: Small-angle X-ray Scatteringmentioning

confidence: 99%

Crystal structures of REF6 and its complex with DNA reveal diverse recognition mechanisms

Tian

et al. 2020

Cell Discov

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Relative of Early Flowing 6 (REF6) is a DNA-sequence-specific H3K27me3/2 demethylase that contains four zinc finger (ZnF) domains and targets several thousand genes in Arabidopsis thaliana. The ZnF domains are essential for binding target genes, but the structural basis remains unclear. Here, we determined crystal structures of the ZnF domains and REF6-DNA complex, revealing a unique REF6-family-specific half-cross-braced ZnF (RCZ) domain and two C2H2-type ZnFs. DNA-binding induces a profound conformational change in the hinge region of REF6. Each REF6 recognizes six bases and DNA methylation reduces the binding affinity. Both the acidic region and basic region are important for the self-association of REF6. The REF6 DNA-binding affinity is determined by the sequence-dependent conformations of DNA and also the cooperativity in different target motifs. The conformational plasticity enables REF6 to function as a global transcriptional regulator that directly binds to many diverse genes, revealing the structural basis for the epigenetic modification recognition.

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Section: Small-angle X-ray Scatteringmentioning

confidence: 99%

Crystal structures of REF6 and its complex with DNA reveal diverse recognition mechanisms

Tian

et al. 2020

Cell Discov

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“…It has been shown that the N-terminal Age1-Age2-KH0 domains of FMRP form Age2 domain-based dimers (Fig. 4b) [37]. Therefore, we examined the isotherm binding data by fitting to different binding models to determine the likely oligomeric state of the protein and the stoichiometry of binding [38].…”

Section: Phosphorylated Kv12 Directly Binds Fmrp In a Dimer-dimer Comentioning

confidence: 99%

Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the Fragile X brain

et al. 2018

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Principal neurons encode information by varying their firing rate and patterns precisely fine-tuned through GABAergic interneurons. Dysregulation of inhibition can lead to neuropsychiatric disorders, yet little is known about the molecular basis underlying inhibitory control. Here, we find that excessive GABA release from basket cells (BCs) attenuates the firing frequency of Purkinje neurons (PNs) in the cerebellum of Fragile X Mental Retardation 1 (Fmr1) knockout (KO) mice, a model of Fragile X Syndrome (FXS) with abrogated expression of the Fragile X Mental Retardation Protein (FMRP). This over-inhibition originates from increased excitability and Ca transients in the presynaptic terminals, where Kv1.2 potassium channels are downregulated. By paired patch-clamp recordings, we further demonstrate that acutely introducing an N-terminal fragment of FMRP into BCs normalizes GABA release in the Fmr1-KO synapses. Conversely, direct injection of an inhibitory FMRP antibody into BCs, or membrane depolarization of BCs, enhances GABA release in the wild type synapses, leading to abnormal inhibitory transmission comparable to the Fmr1-KO neurons. We discover that the N-terminus of FMRP directly binds to a phosphorylated serine motif on the C-terminus of Kv1.2; and that loss of this interaction in BCs exaggerates GABA release, compromising the firing activity of PNs and thus the output from the cerebellar circuitry. An allosteric Kv1.2 agonist, docosahexaenoic acid, rectifies the dysregulated inhibition in vitro as well as acoustic startle reflex and social interaction in vivo of the Fmr1-KO mice. Our results unravel a novel molecular locus for targeted intervention of FXS and perhaps autism.

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“…SAXS experiments. Small-angle X-ray scattering (SAXS) data were collected at the beamline BL19U2 of the SSRF using our previously published methods (34,35). Briefly, all proteins were subjected to size exclusion chromatography with a buffer containing 20 mM Tris-HCl (pH 8.0) and 500 mM NaCl.…”

Section: Methodsmentioning

confidence: 99%

Structural Biology of the Arterivirus nsp11 Endoribonucleases

Zhang

Deng

et al. 2017

J Virol

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Endoribonuclease (NendoU) is unique and conserved as a major genetic marker in nidoviruses that infect vertebrate hosts. Arterivirus nonstructural protein 11 (nsp11) was shown to have NendoU activity and play essential roles in the viral life cycle. Here, we report three crystal structures of porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus (EAV) nsp11 mutants. The structures of arterivirus nsp11 contain two conserved compact domains: the N-terminal domain (NTD) and C-terminal domain (CTD). The structures of PRRSV and EAV endoribonucleases are similar and conserved in the arterivirus, but they are greatly different from that of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses (CoV), representing important human pathogens in the Nidovirales order. The catalytic center of NendoU activity is located in the CTD, where a positively charged groove is next to the key catalytic residues conserved in nidoviruses. Although the NTD is nearly identical, the catalytic region of the arterivirus nsp11 family proteins is remarkably flexible, and the oligomerization may be concentration dependent. In summary, our structures provide new insight into this key multifunctional NendoU family of proteins and lay a foundation for better understanding of the molecular mechanism and antiviral drug development.IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) and equine arteritis virus are two major members of the arterivirus family. PRRSV, a leading swine pathogen, causes reproductive failure in breeding stock and respiratory tract illness in young pigs. Due to the lack of a suitable vaccine or effective drug treatment and the quick spread of these viruses, infected animals either die quickly or must be culled. PRRSV costs the swine industry around $644 million annually in the United States and almost €1.5 billion in Europe every year. To find a way to combat these viruses, we focused on the essential viral nonstructural protein 11 (nsp11). nsp11 is associated with multiple functions, such as RNA processing and suppression of the infected host innate immunity system. The three structures solved in this study provide new insight into the molecular mechanisms of this crucial protein family and will benefit the development of new treatments against these deadly viruses.

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The amino-terminal structure of human fragile X mental retardation protein obtained using precipitant-immobilized imprinted polymers

Cited by 42 publications

References 56 publications

Crystal structures of REF6 and its complex with DNA reveal diverse recognition mechanisms

Crystal structures of REF6 and its complex with DNA reveal diverse recognition mechanisms

Identification of a molecular locus for normalizing dysregulated GABA release from interneurons in the Fragile X brain

Structural Biology of the Arterivirus nsp11 Endoribonucleases

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