Structural basis for tropomyosin overlap in thin (actin) filaments and the generation of a molecular swivel by troponin-T

Head-to-tail polymerization of tropomyosin is crucial for its actin binding, function in actin filament assembly, and the regulation of actin-myosin contraction. Here, we describe the 2.1 Å resolution structure of crystals containing overlapping tropomyosin N and C termini (TM-N and TM-C) and the 2.9 Å resolution structure of crystals containing TM-N and TM-C together with a fragment of troponin-T (TnT). At each junction, the N-terminal helices of TM-N were splayed, with only one of them packing against TM-C. In the C-terminal region of TM-C, a crucial water in the coiled-coil core broke the local 2-fold symmetry and helps generate a kink on one helix. In the presence of a TnT fragment, the asymmetry in TM-C facilitates formation of a 4-helix bundle containing two TM-C chains and one chain each of TM-N and TnT. Mutating the residues that generate the asymmetry in TM-C caused a marked decrease in the affinity of troponin for actin-tropomyosin filaments. The highly conserved region of TnT, in which most cardiomyopathy mutations reside, is crucial for interacting with tropomyosin. The structure of the ternary complex also explains why the skeletal- and cardiac-muscle specific C-terminal region is required to bind TnT and why tropomyosin homodimers bind only a single TnT. On actin filaments, the head-to-tail junction can function as a molecular swivel to accommodate irregularities in the coiled-coil path between successive tropomyosins enabling each to interact equivalently with the actin helix

Metastable Phase Formation from Nd-Dy-Fe-B Undercooled Melt

Abstract Nd 10-x Dy x Fe 85 B 5 (x = 0-3) alloy samples were melted and then solidified in the containerless state of a drop tube at oxygen partial pressure of 10 -1 Pa. The calculated cooling rate of the spherical sample was over 10 3 K/s. The Nd 10 Fe 85 B 5 sample consists of the Nd 2 Fe 17 B x metastable phase together with the α-Fe dendrite. The metastable phase was partially decomposed into small grains of Nd 2 Fe 14 B and α-Fe phases by a solid state decomposition reaction. The substitution of Dy for Nd in the range from 10 to 20 atomic percent was effective to suppress the primary formation of the α-Fe dendrite and to promote the formation of the RE 2 Fe 17 B x metastable phase. When the substitution rate of Dy increased to 30 atomic percent, a large amount of the α-Fe dendrite was formed because an oxide layer of rare earth elements was generated at the sample surface due to the easy oxidization tendency of Dy

Mitochondrial Haplogroup N9a Confers Resistance against Type 2 Diabetes in Asians

Because mitochondria play pivotal roles in both insulin secretion from the pancreatic β cells and insulin resistance of skeletal muscles, we performed a large-scale association study to identify mitochondrial haplogroups that may confer resistance against or susceptibility to type 2 diabetes mellitus (T2DM). The study population comprised 2,906 unrelated Japanese individuals, including 1,289 patients with T2DM and 1,617 controls, and 1,365 unrelated Korean individuals, including 732 patients with T2DM and 633 controls. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups (i.e., F, B, A, N9a, M7a, M7b, G, D4a, D4b, and D5). Multivariate logistic-regression analysis with adjustment for age and sex revealed that the mitochondrial haplogroup N9a was significantly associated with resistance against T2DM (P=.0002) with an odds ratio of 0.55 (95% confidence interval 0.40–0.75). Even in the modern environment, which is often characterized by satiety and physical inactivity, this haplogroup might confer resistance against T2DM