Structural basis for self-association and receptor recognition of human TRAF2

Tumour necrosis factor (TNF)-receptor-associated factors (TRAFs) form a family of cytoplasmic adapter proteins that mediate signal transduction from many members of the TNF-receptor superfamily and the interleukin-1 receptor. They are important in the regulation of cell survival and cell death. The carboxy-terminal region of TRAFs (the TRAF domain) is required for self-association and interaction with receptors. The domain contains a predicted coiled-coil region that is followed by a highly conserved TRAF-C domain. Here we report the crystal structure of the TRAF domain of human TRAF2, both alone and in complex with a peptide from TNF receptor-2 (TNF-R2). The structures reveal a trimeric self-association of the TRAF domain, which we confirm by studies in solution. The TRAF-C domain forms a new, eight-stranded antiparallel beta-sandwich structure. The TNF-R2 peptide binds to a conserved shallow surface depression on one TRAF-C domain and does not contact the other protomers of the trimer. The nature of the interaction indicates that an SXXE motif may be a TRAF2-binding consensus sequence. The trimeric structure of the TRAF domain provides an avidity-based explanation for the dependence of TRAF recruitment on the oligomerization of the receptors by their trimeric extracellular ligands.     

The long and the short of long-term memory--a molecular framework

A single learning event initiates several memory processes with different time courses of retention. While short term memory involves covalent modification of pre-existing proteins, the finding that long-term memory requires the expression, during learning, of additional genes, makes it possible to analyse in molecular terms the induction and retention of long-term memory.     

Inactivation of hCDC4 can cause chromosomal instability

Aneuploidy, an abnormal chromosome number, has been recognized as a hallmark of human cancer for nearly a century; however, the mechanisms responsible for this abnormality have remained elusive. Here we report the identification of mutations in hCDC4 (also known as Fbw7 or Archipelago) in both human colorectal cancers and their precursor lesions. We show that genetic inactivation of hCDC4, by means of targeted disruption of the gene in karyotypically stable colorectal cancer cells, results in a striking phenotype associated with micronuclei and chromosomal instability. This phenotype can be traced to a defect in the execution of metaphase and subsequent transmission of chromosomes, and is dependent on cyclin E--a protein that is regulated by hCDC4 (refs 2-4). Our data suggest that chromosomal instability is caused by specific genetic alterations in a large fraction of human cancers and can occur before malignant conversion.     

The microscopic nature of localization in the quantum Hall effect

The quantum Hall effect arises from the interplay between localized and extended states that form when electrons, confined to two dimensions, are subject to a perpendicular magnetic field. The effect involves exact quantization of all the electronic transport properties owing to particle localization. In the conventional theory of the quantum Hall effect, strong-field localization is associated with a single-particle drift motion of electrons along contours of constant disorder potential. Transport experiments that probe the extended states in the transition regions between quantum Hall phases have been used to test both the theory and its implications for quantum Hall phase transitions. Although several experiments on highly disordered samples have affirmed the validity of the single-particle picture, other experiments and some recent theories have found deviations from the predicted universal behaviour. Here we use a scanning single-electron transistor to probe the individual localized states, which we find to be strikingly different from the predictions of single-particle theory. The states are mainly determined by Coulomb interactions, and appear only when quantization of kinetic energy limits the screening ability of electrons. We conclude that the quantum Hall effect has a greater diversity of regimes and phase transitions than predicted by the single-particle framework. Our experiments suggest a unified picture of localization in which the single-particle model is valid only in the limit of strong disorder.     

Quantum dynamics of a single vortex

Vortices occur naturally in a wide range of gases and fluids, from macroscopic to microscopic scales. In Bose-Einstein condensates of dilute atomic gases, superfluid helium and superconductors, the existence of vortices is a consequence of the quantum nature of the system. Quantized vortices of supercurrent are generated by magnetic flux penetrating the material, and play a key role in determining the material properties and the performance of superconductor-based devices. At high temperatures the dynamics of such vortices are essentially classical, while at low temperatures previous experiments have suggested collective quantum dynamics. However, the question of whether vortex tunnelling occurs at low temperatures has been addressed only for large collections of vortices. Here we study the quantum dynamics of an individual vortex in a superconducting Josephson junction. By measuring the statistics of the vortex escape from a controllable pinning potential, we demonstrate the existence of quantized levels of the vortex energy within the trapping potential well and quantum tunnelling of the vortex through the pinning barrier.     

Bone marrow cells give rise to distinct cell clones within the thymus

The thymus is the major, if not the sole site of maturation of T lymphocytes from their haematopoietic precursors. During embryonic life (at a few well-defined intervals, at least in birds) the thymus receives thymus-homing haematopoietic precursors that give rise to antigen-specific functional T lymphocytes. Although the number and thymic location of distinct T-cell lineages destined to form the peripheral T-cell pool are not yet well defined, at least two independent pathways have been proposed. First, thymic subcapsular lymphoblasts divide and differentiate to give rise to small deep cortical thymic lymphocytes, medullary lymphocytes and thymus emigrants (I.W., unpublished data) and second, the medulla contains an independent self-renewing population that contains the precursors of the peripheral T-cell pool. Following irradiation the thymus may be repopulated by injected haematopoietic cells presumably related to the thymus-homing haematopoietic cells of the embryo. Here we have reconstituted irradiated mice with limiting numbers of bone marrow cells from Thy-1 congeneic donors and have found distinct clones of cells within the thymus. The pattern of reconstitution by the precursor cells indicates that two independent thymus lineages exist: cortex plus medulla, and medulla alone.     

The binary progenitor of Tycho Brahe's 1572 supernova

The brightness of type Ia supernovae, and their homogeneity as a class, makes them powerful tools in cosmology, yet little is known about the progenitor systems of these explosions. They are thought to arise when a white dwarf accretes matter from a companion star, is compressed and undergoes a thermonuclear explosion. Unless the companion star is another white dwarf (in which case it should be destroyed by the mass-transfer process itself), it should survive and show distinguishing properties. Tycho's supernova is one of only two type Ia supernovae observed in our Galaxy, and so provides an opportunity to address observationally the identification of the surviving companion. Here we report a survey of the central region of its remnant, around the position of the explosion, which excludes red giants as the mass donor of the exploding white dwarf. We found a type G0-G2 star, similar to our Sun in surface temperature and luminosity (but lower surface gravity), moving at more than three times the mean velocity of the stars at that distance, which appears to be the surviving companion of the supernova.     

Thermodynamics of the B-Z transition in superhelical DNA

One of the most exciting events in recent years in molecular biology was the discovery of the left-handed Z form of the DNA double helix. Originally found in linear self-complementary d(GC)x . d(GC)x polymers and oligomers in non-physiological conditions (a rather high salt concentration), it was recently shown to be easily enough adopted in physiological conditions when purine-pyrimidine sequences are inserted into superhelical DNA. From such a system, superhelical DNA carrying an artificial purine-pyrimidine insert, we can obtain data allowing the determination of the energy of the junction between the B and Z stretches, Fj, and the free energy change delta FBZ per base pair (bp). We present here a simple thermodynamic consideration of the B-Z transition in such a system. By applying the results to experimental data we have shown that the thermodynamic parameters for both sequences studied so far (d(GC)x . d(GC)x and d(GT)x . d(AC)x) are similar and equal to Fj = 4-5 kcal per mol per junction and delta FBZ = 0.5 divided by 0.7 kcal per mol per bp.     

The colour centre in the cerebral cortex of man

Anatomical and physiological studies have shown that there is an area specialized for the processing of colour (area V4) in the prestriate cortex of macaque monkey brain. Earlier this century, suggestive clinical evidence for a colour centre in the brain of man was dismissed because of the association of other visual defects with the defects in colour vision. However, since the demonstration of functional specialization in the macaque cortex, the question of a colour centre in man has been reinvestigated, based on patients with similar lesions in the visual cortex. In order to study the colour centre in normal human subjects, we used the technique of positron emission tomography (PET), which measures increases in blood flow resulting from increased activity in the cerebral cortex. A comparison of the results of PET scans of subjects viewing multi-coloured and black-and-white displays has identified a region of normal human cerebral cortex specialized for colour vision.     

Substitution at residue 227 of H-2 class I molecules abrogates recognition by CD8-dependent, but not CD8-independent, cytotoxic T lymphocytes

The CD8 (Lyt 2) molecule is a phenotypic marker for T lymphocytes that recognize and react with major histocompatibility complex (MHC) class I molecules. Antibody blocking experiments and gene transfection studies indicate that CD8 binds to a determinant on MHC class I molecules on the target cells, facilitating interaction between effector T lymphocytes and the target cell. The CD8 molecule may also be involved in transmembrane signalling during T-cell activation. The existence of CD8- cytotoxic T lymphocytes (CTL) and class I-reactive CTL that are not inhibited by antibody to CD8 suggests that at least some CTL do not require the CD8 molecule to interact with and lyse target cells. We have recently demonstrated that cells transfected with an H-2Dd gene that carries a mutation at residue 227 are not killed by primary CTL8. Here we show that although this mutation abrogates recognition by primary CTL, it does not affect recognition by CD8-independent CTL, suggesting that residue 227 of class I molecules might contribute to a determinant that is the ligand of the CD8 molecule.