The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia

Seven Fanconi anemia-associated proteins (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL) form a nuclear Fanconi anemia core complex that activates the monoubiquitination of FANCD2, targeting FANCD2 to BRCA1-containing nuclear foci. Cells from individuals with Fanconi anemia of complementation groups D1 and J (FA-D1 and FA-J) have normal FANCD2 ubiquitination. Using genetic mapping, mutation identification and western-blot data, we identify the defective protein in FA-J cells as BRIP1 (also called BACH1), a DNA helicase that is a binding partner of the breast cancer tumor suppressor BRCA1.     

Overview of the Alliance for Cellular Signaling

The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells--B lymphocytes (the cells of the immune system) and cardiac myocytes--to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.     

A three-dimensional optical photonic crystal with designed point defects

Photonic crystals offer unprecedented opportunities for miniaturization and integration of optical devices. They also exhibit a variety of new physical phenomena, including suppression or enhancement of spontaneous emission, low-threshold lasing, and quantum information processing. Various techniques for the fabrication of three-dimensional (3D) photonic crystals--such as silicon micromachining, wafer fusion bonding, holographic lithography, self-assembly, angled-etching, micromanipulation, glancing-angle deposition and auto-cloning--have been proposed and demonstrated with different levels of success. However, a critical step towards the fabrication of functional 3D devices, that is, the incorporation of microcavities or waveguides in a controllable way, has not been achieved at optical wavelengths. Here we present the fabrication of 3D photonic crystals that are particularly suited for optical device integration using a lithographic layer-by-layer approach. Point-defect microcavities are introduced during the fabrication process and optical measurements show they have resonant signatures around telecommunications wavelengths (1.3-1.5 microm). Measurements of reflectance and transmittance at near-infrared are in good agreement with numerical simulations.     

Cis-trans isomerization at a proline opens the pore of a neurotransmitter-gated ion channel

5-hydroxytryptamine type 3 (5-HT3) receptors are members of the Cys-loop receptor superfamily. Neurotransmitter binding in these proteins triggers the opening (gating) of an ion channel by means of an as-yet-uncharacterized conformational change. Here we show that a specific proline (Pro 8*), located at the apex of the loop between the second and third transmembrane helices (M2-M3), can link binding to gating through a cis-trans isomerization of the protein backbone. Using unnatural amino acid mutagenesis, a series of proline analogues with varying preference for the cis conformer was incorporated at the 8* position. Proline analogues that strongly favour the trans conformer produced non-functional channels. Among the functional mutants there was a strong correlation between the intrinsic cis-trans energy gap of the proline analogue and the activation of the channel, suggesting that cis-trans isomerization of this single proline provides the switch that interconverts the open and closed states of the channel. Consistent with this proposal, nuclear magnetic resonance studies on an M2-M3 loop peptide reveal two distinct, structured forms. Our results thus confirm the structure of the M2-M3 loop and the critical role of Pro 8* in the 5-HT3 receptor. In addition, they suggest that a molecular rearrangement at Pro 8* is the structural mechanism that opens the receptor pore.