Cysteine 230 is essential for the structure and activity of the cytotoxic ligand TRAIL.

Unlike other tumor necrosis factor family members, the cytotoxic ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo-2L contains an unpaired cysteine residue (Cys(230)) in its receptor-binding domain. Here we show that the biological activity of both soluble recombinant TRAIL and cell-associated, full-length TRAIL is critically dependent on the presence of Cys(230). Mutation of Cys(230) to alanine or serine strongly affected its ability to kill target cells. Binding to its receptors was decreased by at least 200-fold, and the stability of its trimeric structure was reduced. In recombinant TRAIL, Cys(230) was found engaged either in interchain disulfide bridge formation, resulting in poorly active TRAIL, or in the chelation of one zinc atom per TRAIL trimer in the active, pro-apoptotic form of TRAIL

Inhibition of death receptor signals by cellular FLIP.

The widely expressed protein Fas is a member of the tumour necrosis factor receptor family which can trigger apoptosis. However, Fas surface expression does not necessarily render cells susceptible to Fas ligand-induced death signals, indicating that inhibitors of the apoptosis-signalling pathway must exist. Here we report the characterization of an inhibitor of apoptosis, designated FLIP (for FLICE-inhibitory protein), which is predominantly expressed in muscle and lymphoid tissues. The short form, FLIPs, contains two death effector domains and is structurally related to the viral FLIP inhibitors of apoptosis, whereas the long form, FLIP(L), contains in addition a caspase-like domain in which the active-centre cysteine residue is substituted by a tyrosine residue. FLIPs and FLIP(L) interact with the adaptor protein FADD and the protease FLICE, and potently inhibit apoptosis induced by all known human death receptors. FLIP(L) is expressed during the early stage of T-cell activation, but disappears when T cells become susceptible to Fas ligand-mediated apoptosis. High levels of FLIP(L) protein are also detectable in melanoma cell lines and malignant melanoma tumours. Thus FLIP may be implicated in tissue homeostasis as an important regulator of apoptosis

Neutron star properties in the quark-meson coupling model

The effects of internal quark structure of baryons on the composition and structure of neutron star matter with hyperons are investigated in the quark-meson coupling (QMC) model. The QMC model is based on mean-field description of nonoverlapping spherical bags bound by self-consistent exchange of scalar and vector mesons. The predictions of this model are compared with quantum hadrodynamic (QHD) model calibrated to reproduce identical nuclear matter saturation properties. By employing a density dependent bag constant through direct coupling to the scalar field, the QMC model is found to exhibit identical properties as QHD near saturation density. Furthermore, this modified QMC model provides well-behaved and continuous solutions at high densities relevant to the core of neutron stars. Two additional strange mesons are introduced which couple only to the strange quark in the QMC model and to the hyperons in the QHD model. The constitution and structure of stars with hyperons in the QMC and QHD models reveal interesting differences. This suggests the importance of quark structure effects in the baryons at high densities.Comment: 28 pages, 10 figures, to appear in Physical Review

Four-body cluster structure of A=7−10A=7-10 double-Λ\Lambda hypernuclei

Energy levels of the double-$\Lambda$ hypernuclei $_\Lambda^{}$$_\Lambda^7$He, $_\Lambda^{}$$_\Lambda^7$Li, $_\Lambda^{}$$_\Lambda^8$Li, $_\Lambda^{}$$_\Lambda^9$Li, $_\Lambda^{}$$_\Lambda^9$Be and $_\Lambda^{}$$_\Lambda^{10}$Be are predicted on the basis of the $\alpha+x+\Lambda +\Lambda$ four-body model with $x=n, p, d, t, ^3$He and $\alpha$, respectively.Comment: 27 pages (preprint style), 12figures submitted to Phys. Rev.

Genetic defects in common variable immunodeficiency

Common variable immunodeficiency (CVID) is the most frequent clinically manifested primary immunodeficiency. According to clinical and laboratory findings, CVID is a heterogeneous group of diseases. Recently, the defects of molecules regulating activation and terminal differentiation of B lymphocytes have been described in some patients with CVID. In this study, we show the overview of deficiencies of inducible costimulator, transmembrane activator and calcium-modulator and cytophilin ligand interactor, CD19 molecules, their genetic basis, pathogenesis and clinical manifestations

Integrating sequence and array data to create an improved 1000 Genomes Project haplotype reference panel

A major use of the 1000 Genomes Project (1000GP) data is genotype imputation in genome-wide association studies (GWAS). Here we develop a method to estimate haplotypes from low-coverage sequencing data that can take advantage of single-nucleotide polymorphism (SNP) microarray genotypes on the same samples. First the SNP array data are phased to build a backbone (or 'scaffold') of haplotypes across each chromosome. We then phase the sequence data 'onto' this haplotype scaffold. This approach can take advantage of relatedness between sequenced and non-sequenced samples to improve accuracy. We use this method to create a new 1000GP haplotype reference set for use by the human genetic community. Using a set of validation genotypes at SNP and bi-allelic indels we show that these haplotypes have lower genotype discordance and improved imputation performance into downstream GWAS samples, especially at low-frequency variants. © 2014 Macmillan Publishers Limited. All rights reserved

The molecular architecture of the TNF superfamily.

Ligands of the TNF (tumour necrosis factor) superfamily have pivotal roles in the organization and function of the immune system, and are implicated in the aetiology of several acquired and genetic diseases. TNF ligands share a common structural motif, the TNF homology domain (THD), which binds to cysteine-rich domains (CRDs) of TNF receptors. CRDs are composed of structural modules, whose variation in number and type confers heterogeneity upon the family. Protein folds reminiscent of the THD and CRD are also found in other protein families, raising the possibility that the mode of interaction between TNF and TNF receptors might be conserved in other contexts

Development of improved soluble inhibitors of FasL and CD40L based on oligomerized receptors.

TNF receptor family members fused to the constant domain of immunoglobulin G have been widely used as immunoadhesins in basic in vitro and in vivo research and in some clinical applications. In this study, we assemble soluble, high avidity chimeric receptors on a pentameric scaffold derived from the coiled-coil domain of cartilage oligomeric matrix protein (COMP). The affinity of Fas and CD40 (but not TNFR-1 and TRAIL-R2) to their ligands is increased by fusion to COMP, when compared to the respective Fc chimeras. In functional assays, Fas:COMP was at least 20-fold more active than Fas:Fc at inhibiting the action of sFasL, and CD40:COMP could block CD40L-mediated proliferation of B cells, whereas CD40:Fc could not. In conclusion, members of the TNF receptor family can display high specificity and excellent avidity for their ligands if they are adequately multimerized