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.     

Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes

Metformin is the most commonly used pharmacological therapy for type 2 diabetes. We report a genome-wide association study for glycemic response to metformin in 1,024 Scottish individuals with type 2 diabetes with replication in two cohorts including 1,783 Scottish individuals and 1,113 individuals from the UK Prospective Diabetes Study. In a combined meta-analysis, we identified a SNP, rs11212617, associated with treatment success (n = 3,920, P = 2.9 × 10(-9), odds ratio = 1.35, 95% CI 1.22-1.49) at a locus containing ATM, the ataxia telangiectasia mutated gene. In a rat hepatoma cell line, inhibition of ATM with KU-55933 attenuated the phosphorylation and activation of AMP-activated protein kinase in response to metformin. We conclude that ATM, a gene known to be involved in DNA repair and cell cycle control, plays a role in the effect of metformin upstream of AMP-activated protein kinase, and variation in this gene alters glycemic response to metformin.     

Synthesis and breakdown of proteins and ribonucleic acid inTribolium confusum,Duval

Résumé Dans notre étude, l'incorporation de la leucine-C¹⁴ dans les protéines et de l'uridine-C¹⁴ dans le RNA chez leTribolium confusum s'est révélée maximale durant la phase la plus active de croissance, et minimale durant la phase de pupe, pendant laquelle l'animal ne mange pas. La synthèse du RNA précède celle des protéines, tel que prévu. Nos résultats montrent aussi une continuelle dégradation des protéines par des protéases intra-cellulaires et du RNA par des RNases.     

Tethys and Dione as sources of outward-flowing plasma in Saturn's magnetosphere

Rotating at over twice the angular speed of Earth, Saturn imposes a rapid spin on its magnetosphere. As a result, cold, dense plasma is believed to be flung outward from the inner magnetosphere by centrifugal force and replaced by hotter, more tenuous plasma from the outer magnetosphere. The centrifugal interchange of plasmas in rotating magnetospheres was predicted many years ago and was conclusively demonstrated by observations in Jupiter's magnetosphere, which--like that of Saturn (but unlike that of Earth)--is rotationally dominated. Recent observations in Saturn's magnetosphere have revealed narrow injections of hot, tenuous plasma believed to be the inward-moving portion of the centrifugal interchange cycle. Here we report observations of the distribution of the angle between the electron velocity vector and the magnetic field vector ('pitch angle') obtained in the cold, dense plasma adjacent to these inward injection regions. The observed pitch-angle distributions are indicative of outward plasma flow and consistent with centrifugal interchange in Saturn's magnetosphere. Further, we conclude that the observed double-peaked ('butterfly') pitch-angle distributions result from the transport of plasma from regions near the orbits of Dione and Tethys, supporting the idea of distinct plasma tori associated with these moons.     

Lessons on the pathogenesis of aneurysm from heritable conditions

Aortic aneurysm is common, accounting for 1-2% of all deaths in industrialized countries. Early theories of the causes of human aneurysm mostly focused on inherited or acquired defects in components of the extracellular matrix in the aorta. Although several mutations in the genes encoding extracellular matrix proteins have been recognized, more recent discoveries have shown important perturbations in cytokine signalling cascades and intracellular components of the smooth muscle contractile apparatus. The modelling of single-gene heritable aneurysm disorders in mice has shown unexpected involvement of the transforming growth factor-β cytokine pathway in aortic aneurysm, highlighting the potential for new therapeutic strategies.