Structural basis of transcription regulation by CNC family transcription factor, Nrf2.

Several basic leucine zipper (bZIP) transcription factors have accessory motifs in their DNA-binding domains, such as the CNC motif of CNC family or the EHR motif of small Maf (sMaf) proteins. CNC family proteins heterodimerize with sMaf proteins to recognize CNC-sMaf binding DNA elements (CsMBEs) in competition with sMaf homodimers, but the functional role of the CNC motif remains elusive. In this study, we report the crystal structures of Nrf2/NFE2L2, a CNC family protein regulating anti-stress transcriptional responses, in a complex with MafG and CsMBE. The CNC motif restricts the conformations of crucial Arg residues in the basic region, which form extensive contact with the DNA backbone phosphates. Accordingly, the Nrf2-MafG heterodimer has approximately a 200-fold stronger affinity for CsMBE than canonical bZIP proteins, such as AP-1 proteins. The high DNA affinity of the CNC-sMaf heterodimer may allow it to compete with the sMaf homodimer on target genes without being perturbed by other low-affinity bZIP proteins with similar sequence specificity.

Human nonsense-mediated mRNA decay factor UPF2 interacts directly with eRF3 and the SURF complex.

Nonsense-mediated mRNA decay (NMD) is an mRNA degradation pathway that regulates gene expression and mRNA quality. A complex network of macromolecular interactions regulates NMD initiation, which is only partially understood. According to prevailing models, NMD begins by the assembly of the SURF (SMG1-UPF1-eRF1-eRF3) complex at the ribosome, followed by UPF1 activation by additional factors such as UPF2 and UPF3. Elucidating the interactions between NMD factors is essential to comprehend NMD, and here we demonstrate biochemically and structurally the interaction between human UPF2 and eukaryotic release factor 3 (eRF3). In addition, we find that UPF2 associates with SURF and ribosomes in cells, in an UPF3-independent manner. Binding assays using a collection of UPF2 truncated variants reveal that eRF3 binds to the C-terminal part of UPF2. This region of UPF2 is partially coincident with the UPF3-binding site as revealed by electron microscopy of the UPF2-eRF3 complex. Accordingly, we find that the interaction of UPF2 with UPF3b interferes with the assembly of the UPF2-eRF3 complex, and that UPF2 binds UPF3b more strongly than eRF3. Together, our results highlight the role of UPF2 as a platform for the transient interactions of several NMD factors, including several components of SURF.

A novel allosteric mechanism on protein-DNA interactions underlying the phosphorylation-dependent regulation of Ets1 target gene expressions.

Cooperative assemblies of transcription factors (TFs) on target gene enhancers coordinate cell proliferation, fate specification, and differentiation through precise and complicated transcriptional mechanisms. Chemical modifications, such as phosphorylation, of TFs induced by cell signaling further modulate the dynamic cooperativity of TFs. In this study, we found that various Ets1-containing TF-DNA complexes respond differently to calcium-induced phosphorylation of Ets1, which is known to inhibit Ets1-DNA binding. Crystallographic analysis of a complex comprising Ets1, Runx1, and CBFß at the TCRα enhancer revealed that Ets1 acquires robust binding stability in the Runx1 and DNA-complexed state, via allosteric mechanisms. This allows phosphorylated Ets1 to be retained at the TCRα enhancer with Runx1, in contrast to other Ets1 target gene enhancers including mb-1 and stromelysin-1. This study provides a structure-based model for cell-signaling-dependent regulation of target genes, mediated via chemical modification of TFs.

Structures of SMG1-UPFs complexes: SMG1 contributes to regulate UPF2-dependent activation of UPF1 in NMD.

SMG1, a PI3K-related kinase, plays a critical role in nonsense-mediated mRNA decay (NMD) in mammals. SMG1-mediated phosphorylation of the UPF1 helicase is an essential step during NMD initiation. Both SMG1 and UPF1 are presumably activated by UPF2, but this regulation is incompletely understood. Here we reveal that SMG1C (a complex containing SMG1, SMG8, and SMG9) contributes to regulate NMD by recruiting UPF1 and UPF2 to distinct sites in the vicinity of the kinase domain. UPF2 binds SMG1 in an UPF1-independent manner in vivo, and the SMG1C-UPF2 structure shows UPF2 recognizes the FRB domain, a region that regulates the related mTOR kinase. The molecular architectures of several SMG1C-UPFs complexes, obtained by combining electron microscopy with in vivo and in vitro interaction analyses, competition experiments, and mutations, suggest that UPF2 can be transferred to UPF1 within SMG1C, inducing UPF2-dependent conformational changes required to activate UPF1 within an SMG1C-UPF1-UPF2 complex.

Event-related differences in the cross-sectional areas and torque generation capabilities of quadriceps femoris and hamstrings in male high school athletes.

This study investigated the event-related differences in the cross-sectional areas (CSAs) and torque generation capabilities of the quadriceps femoris (QF) and hamstrings (HAM) in male high school athletes. Subjects were soccer players (n=32), volleyball players (21), rowers (29), karate athletes (18), sumo wrestlers (15), sprinters (22), throwers (16), and nonathletes (20). The CSAs of QF and HAM at the mid-thigh were determined using magnetic resonance imaging. In addition, isokinetic torques during knee extension and flexion were determined at a pre-set velocity of 1.05 rad/s. The CSAs of the two muscle groups and torques developed in the two motions were significantly related to the two-third power of lean body mass (LBM(2/3)) and the product of CSA and femur length (CSA*fl), calculated as an index of muscle volume, respectively. CSA relative to LBM(2/3) for QF did not differ among the groups, but that for HAM was higher in sprinters, soccer players, throwers, and karate athletes than in sumo wrestlers, rowers, volleyball players, and nonathletes. Knee extension torque relative to the CSA*fl of QF was higher in karate athletes, soccer players, and rowers than in nonathletes, but the corresponding value for knee flexion did not differ among groups. Thus, the present study indicated that, at least in male high school athletes, the event-related differences in LBM and the muscularity of QF and HAM produced the corresponding differences in the CSAs of the reciprocal muscle groups and knee extension and flexion torques, respectively. However, specific profiles related to competitive and/or training styles exist in HAM CSA and knee extension torque, which cannot be explained by the magnitude of LBM and QF CSA, respectively.

Influence of the psoas major and thigh muscularity on 100-m times in junior sprinters.

PURPOSE: This study aimed to investigate how the cross-sectional areas (CSA) of the quadriceps femoris (QF)3, hamstrings (Ham), and psoas major (PM) in junior sprinters are related to mean running velocity (MV100m) calculated from official records of 100-m races. METHODS: In 44 sprinters (22 boys and 22 girls) aged 14-17 yr, cross-sectional images were taken at the upper thigh and midthigh and midway between the fourth and fifth lumbar vertebrae using magnetic resonance imaging. CSA of the three muscles located in both sides were analyzed. For each muscle, the mean values of the CSA of the right and left sides were calculated and used for regression analyses of the relationships between CSA variables and MV100m. RESULTS: Stepwise multiple-regression analyses produced prediction equations of MV100m with independent variables of QF CSA at the midthigh and PM-to-QF CSA ratio at the upper thigh for boys (R = 0.38) and PM-to-QF CSA ratio at the midthigh for girls (R = 0.33). In the regression model for boys, QF CSA at the midthigh had a negative regression coefficient. CONCLUSION: For junior sprinters of both genders, the higher development of PM relative to QF, rather than absolute muscle size, is a factor in achieving a better performance in 100-m race performance.

[Rehabilitation for gait and activity of daily livings at home: an informed form for Parkinson's disease patients].

Rehabilitation aims to provide patients and their supporters with the knowledge, skills and support necessary to maintain their autonomy, minimize disability and maximize the level of participation of individual. This may be the case in Parkinson's disease (PD) patients. However, to our knowledge, previous papers concerning rehabilitation for PD patients have been not easily to understand and not suit for usage in clinical activities. In this review, we provide comprehensive explanations for daily rehabilitation in their habitation for PD patients and doctors.