Structure of the insulin receptor ectodomain reveals a folded-over conformation

The insulin receptor is a phylogenetically ancient tyrosine kinase receptor found in organisms as primitive as cnidarians and insects. In higher organisms it is essential for glucose homeostasis, whereas the closely related insulin-like growth factor receptor (IGF-1R) is involved in normal growth and development. The insulin receptor is expressed in two isoforms, IR-A and IR-B; the former also functions as a high-affinity receptor for IGF-II and is implicated, along with IGF-1R, in malignant transformation. Here we present the crystal structure at 3.8 A resolution of the IR-A ectodomain dimer, complexed with four Fabs from the monoclonal antibodies 83-7 and 83-14 (ref. 4), grown in the presence of a fragment of an insulin mimetic peptide. The structure reveals the domain arrangement in the disulphide-linked ectodomain dimer, showing that the insulin receptor adopts a folded-over conformation that places the ligand-binding regions in juxtaposition. This arrangement is very different from previous models. It shows that the two L1 domains are on opposite sides of the dimer, too far apart to allow insulin to bind both L1 domains simultaneously as previously proposed. Instead, the structure implicates the carboxy-terminal surface of the first fibronectin type III domain as the second binding site involved in high-affinity binding.     

The effect of cyclic AMP on dog renal function

The infusion of dibutyryl-cyclic AMP into the dog renal artery in vivo leads to diuresis, natriuresis and glucosuria. Addition of the nucleotide to the incubation medium bathing dog renal cortex slices in vitro causes inhibition of p-amino-hippurate accumulation and stimulation of glycine and beta-methyl-glucoside transport. The results are interpreted in terms of the development of a blood-lumen flux of sodium and water in the renal proximal tubule, analogous to that seen in the intestine.     

Identification of self peptides bound to purified HLA-B27

A pool of endogenous peptides bound to the human class I MHC molecule, HLA-B27, has been isolated. Microsequence analysis of the pool and of 11 HPLC-purified peptides provides information on the binding specificity of the HLA-B27 molecule. The peptides all seem to be nonamers, seven of which match to protein sequences in a database search. These self peptides derive from abundant cytosolic or nuclear proteins, such as histone, ribosomal proteins, and members of the 90K heat-shock protein family.     

Genetic structure and division of labor in honeybee societies

Summary Recent studies have demonstrated a genotypic component to the division of labor among worker honeybees. However, these studies used artificially-selected strains of bees or colonies derived from queens that were instrumentally inseminated with the semen from very few males. We present evidence for genotypic variability among groups of workers performing tasks in colonies with naturally-mated queens. These results demonstrate that genetic structure is a level of social organization in honeybees.     

Effect of different bathing media on the short-circuit current across the intestine of the rat and guinea-pig.

The changes in short-circuit current occurring when one or both solutions bathing the intestine of rat or guinea-pig mounted in flux chambers were recorded. The results with the guinea-pig can be explained in terms of diffusion potentials arising from the ionic replacements, and an electrogenic sodium pump, sensitive to ouabain, in the contraluminal membrane of the cell. In the rat, the situation is more complicated, and the enterocyte probably possesses an electrogenic sodium pump in the brush-border membrane.     

DISC1-dependent switch from progenitor proliferation to migration in the developing cortex

Regulatory mechanisms governing the sequence from progenitor cell proliferation to neuronal migration during corticogenesis are poorly understood. Here we report that phosphorylation of DISC1, a major susceptibility factor for several mental disorders, acts as a molecular switch from maintaining proliferation of mitotic progenitor cells to activating migration of postmitotic neurons in mice. Unphosphorylated DISC1 regulates canonical Wnt signalling via an interaction with GSK3β, whereas specific phosphorylation at serine 710 (S710) triggers the recruitment of Bardet-Biedl syndrome (BBS) proteins to the centrosome. In support of this model, loss of BBS1 leads to defects in migration, but not proliferation, whereas DISC1 knockdown leads to deficits in both. A phospho-dead mutant can only rescue proliferation, whereas a phospho-mimic mutant rescues exclusively migration defects. These data highlight a dual role for DISC1 in corticogenesis and indicate that phosphorylation of this protein at S710 activates a key developmental switch.     

Structural basis for the subunit assembly of the anaphase-promoting complex

The anaphase-promoting complex or cyclosome (APC/C) is an unusually large E3 ubiquitin ligase responsible for regulating defined cell cycle transitions. Information on how its 13 constituent proteins are assembled, and how they interact with co-activators, substrates and regulatory proteins is limited. Here, we describe a recombinant expression system that allows the reconstitution of holo APC/C and its sub-complexes that, when combined with electron microscopy, mass spectrometry and docking of crystallographic and homology-derived coordinates, provides a precise definition of the organization and structure of all essential APC/C subunits, resulting in a pseudo-atomic model for 70% of the APC/C. A lattice-like appearance of the APC/C is generated by multiple repeat motifs of most APC/C subunits. Three conserved tetratricopeptide repeat (TPR) subunits (Cdc16, Cdc23 and Cdc27) share related superhelical homo-dimeric architectures that assemble to generate a quasi-symmetrical structure. Our structure explains how this TPR sub-complex, together with additional scaffolding subunits (Apc1, Apc4 and Apc5), coordinate the juxtaposition of the catalytic and substrate recognition module (Apc2, Apc11 and Apc10 (also known as Doc1)), and TPR-phosphorylation sites, relative to co-activator, regulatory proteins and substrates.     

Longitudinal development of macroinvertebrate communities below oligotrophic lake outlets

Benthic macroinvertebrates were collected at several sites downstream of three oligotrophic lake outfalls in July 1986. Total numbers, biomass, and species richness increased rapidly immediately downstream from the outlets and then either stabilized or continued to increase downstream in parallel with benthic organic matter standing crops. Filter feeder densities showed an initial buildup and then decline downstream from the outlets. Variability in longitudinal patterns of other functional feeding groups among lake outlets was related to differences in food quantity and quality, and microhabitat. An additional set of samples was collected at Pettit Lake outlet in August 1986. Species richness and total density peaked sooner under baseflow conditions in August than under spring runoff conditions in June. Distributions of all functional feeding groups, except filter feeders, also differed between the two periods, reflecting differences in the physical environment. We conclude that reduced lentic inputs of particulate organic matter seston and improved habitat suitability downstream are responsible for the progressive development of macroinvertebrate communities in oligotrophic lake outlets. These data imply the importance of the habitat templet in the structuring of benthic communities.