Aire induces ectopic expression of peripheral tissue antigens (PTAs) in thymic medullary epithelial cells, which promotes immunological tolerance. Beginning with a broad screen of histone peptides, we demonstrate that the mechanism by which this single factor controls the transcription of thousands of genes involves recognition of the amino-terminal tail of histone H3, but not of other histones, by one of Aire's plant homeodomain (PHD) fingers. Certain posttranslational modifications of H3 tails, notably dimethylation or trimethylation at H3K4, abrogated binding by Aire, whereas others were tolerated. Similar PHD finger-H3 tail-binding properties were recently reported for BRAF-histone deacetylase complex 80 and DNA methyltransferase 3L; sequence alignment, molecular modeling, and biochemical analyses showed these factors and Aire to have structure-function relationships in common. In addition, certain PHD1 mutations underlying the polyendocrine disorder autoimmune polyendocrinopathy-candidiasesectodermaldystrophy compromised Aire recognition of H3. In vitro binding assays demonstrated direct physical interaction between Aire and nucleosomes, which was in part buttressed by its affinity to DNA. In vivo Aire interactions with chromosomal regions depleted of H3K4me3 were dependent on its H3 tail-binding activity, and this binding was necessary but not sufficient for the up-regulation of genes encoding PTAs. Thus, Aire's activity as a histone-binding module mediates the thymic display of PTAs that promotes self-tolerance and prevents organ-specific autoimmunity.T cell tolerance ͉ plant homeodomain finger ͉ thymus ͉ APS-1 ͉ APECED

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Signal transduction underlying bacterial chemotaxis involves excitatory phosphorylation and feedback control through deamidation and methylation of sensory receptors. The structure of a complex between the signal-terminating phosphatase, CheC, and the receptor-modifying deamidase, CheD, reveals how CheC mimics receptor substrates to inhibit CheD and how CheD stimulates CheC phosphatase activity. CheD resembles other cysteine deamidases from bacterial pathogens that inactivate host Rho-GTPases. CheD not only deamidates receptor glutamine residues contained within a conserved structural motif but also hydrolyzes glutamyl-methyl-esters at select regulatory positions. Substituting Gln into the receptor motif of CheC turns the inhibitor into a CheD substrate. Phospho-CheY, the intracellular signal and CheC target, stabilizes the CheC:CheD complex and reduces availability of CheD. A point mutation that dissociates CheC from CheD impairs chemotaxis in vivo. Thus, CheC incorporates an element of an upstream receptor to influence both its own effect on receptor output and that of its binding partner, CheD.

Novel A-to-I RNA editing in the coding sequence of RHOQ leads to an amino acid substitution that promotes invasion in colorectal cancer.

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API5 (APoptosis Inhibitor 5) and nuclear FGF2 (Fibroblast Growth Factor 2) are upregulated in various human cancers and are correlated with poor prognosis. Although their physical interaction has been identified, the function related to the resulting complex is unknown. Here, we determined the crystal structure of the API5–FGF2 complex and identified critical residues driving the protein interaction. These findings provided a structural basis for the nuclear localization of the FGF2 isoform lacking a canonical nuclear localization signal and identified a cryptic nuclear localization sequence in FGF2. The interaction between API5 and FGF2 was important for mRNA nuclear export through both the TREX and eIF4E/LRPPRC mRNA export complexes, thus regulating the export of bulk mRNA and specific mRNAs containing eIF4E sensitivity elements, such as c-MYC and cyclin D1. These data show the newly identified molecular function of API5 and nuclear FGF2, and provide a clue to understanding the dynamic regulation of mRNA export.

Human head and body lice attach their eggs respectively to human hair or clothing by female lice secreted glue that hardens into a nit sheath that protects the egg. In this study, a series of experiments were conducted to characterize the glue-like material of the nit sheath. Fourier transform infrared spectroscopy on embryo-cleared nit showed proteinaceous amide I bands. With this result, we determined the amino acid composition of the nit sheath proteins and performed similarity search against the protein products of the body louse genome to identify the candidate nit sheath proteins. The identified two homologous proteins newly named as louse nit sheath protein (LNSP) 1 and LNSP2 are composed of three domains of characteristic repeating sequences. The N-terminal and middle domains consist of tandem two-residue repeats of Gln-Ala and Gly-Ala, respectively, which are expected to fold into β-strands and may further stack into β-sheets, whereas the C-terminal domain contains multiple consecutive Gln residues. Temporal and spatial transcription profiling demonstrated that both LNSP1 and LNSP2 are most predominantly expressed in the accessory gland of females of egg-laying stage, supporting that they indeed encode the nit sheath proteins. Further adhesive property of recombinant partial LNSP1 suggests that both LNSP1 and LNSP2 may act as glues.

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