Intrinsic dynamics of an enzyme underlies catalysis

A unique feature of chemical catalysis mediated by enzymes is that the catalytically reactive atoms are embedded within a folded protein. Although current understanding of enzyme function has been focused on the chemical reactions and static three-dimensional structures, the dynamic nature of proteins has been proposed to have a function in catalysis. The concept of conformational substates has been described; however, the challenge is to unravel the intimate linkage between protein flexibility and enzymatic function. Here we show that the intrinsic plasticity of the protein is a key characteristic of catalysis. The dynamics of the prolyl cis-trans isomerase cyclophilin A (CypA) in its substrate-free state and during catalysis were characterized with NMR relaxation experiments. The characteristic enzyme motions detected during catalysis are already present in the free enzyme with frequencies corresponding to the catalytic turnover rates. This correlation suggests that the protein motions necessary for catalysis are an intrinsic property of the enzyme and may even limit the overall turnover rate. Motion is localized not only to the active site but also to a wider dynamic network. Whereas coupled networks in proteins have been proposed previously, we experimentally measured the collective nature of motions with the use of mutant forms of CypA. We propose that the pre-existence of collective dynamics in enzymes before catalysis is a common feature of biocatalysts and that proteins have evolved under synergistic pressure between structure and dynamics.     

河北大麻坪超基性岩包体的岩石组构和地震波速各向异性

通过系统测定大麻坪尖晶石二辉橄榄岩、尖晶石方辉橄榄岩和含长二辉岩三类超基性岩包体中各主要矿物的晶格优选方位（LPO）,并用理论计算和实验测量得出地震波在岩石不同方向上的传播速度。结果表明：1）大麻坪包体中橄榄石与斜方辉石的LPO方位关系与通常所见的[100]ol//[001]opx,[010]ol//[100]opx,[001]ol//[010]opx不同;2）大麻坪地区幔源包体的波速各向异性显著,岩石的波速各向异性特征与其宏观构造和微观组构一致,说明岩石组构是赞成地震波速各向异性的决定因素;3）由地震波速推测的大麻坪地区的上地幔成分与包体出露的情况一致,即主体为二辉橄榄岩。     

Charon's radius and atmospheric constraints from observations of a stellar occultation

The physical characteristics of Pluto and its moon, Charon, provide insight into the evolution of the outer Solar System. Although previous measurements have constrained the masses of these bodies, their radii and densities have remained uncertain. The observation of a stellar occultation by Charon in 1980 established a lower limit on its radius of 600 km (ref. 3) (later refined to 601.5 km; ref. 4) and suggested a possible atmosphere. Subsequent, mutual event modelling yielded a range of 600-650 km (ref. 5), corresponding to a density of 1.56 +/- 0.22 g cm(-3) (refs 2, 5). Here we report multiple-station observations of a stellar occultation by Charon. From these data, we find a mean radius of 606 +/- 8 km, a bulk density of 1.72 +/- 0.15 g cm(-3), and rock-mass fraction 0.63 +/- 0.05. We do not detect a significant atmosphere and place 3sigma upper limits on atmospheric number densities for candidate gases. These results seem to be consistent with collisional formation for the Pluto-Charon system in which the precursor objects may have been differentiated, and they leave open the possibility of atmospheric retention by the largest objects in the outer Solar System.     

Disruption of CREB function in brain leads to neurodegeneration

Control of cellular survival and proliferation is dependent on extracellular signals and is a prerequisite for ordered tissue development and maintenance. Activation of the cAMP responsive element binding protein (CREB) by phosphorylation has been implicated in the survival of mammalian cells. To define its roles in the mouse central nervous system, we disrupted Creb1 in brain of developing and adult mice using the Cre/loxP system. Mice with a Crem(-/-) background and lacking Creb in the central nervous system during development show extensive apoptosis of postmitotic neurons. By contrast, mice in which both Creb1 and Crem are disrupted in the postnatal forebrain show progressive neurodegeneration in the hippocampus and in the dorsolateral striatum. The striatal phenotype is reminiscent of Huntington disease and is consistent with the postulated role of CREB-mediated signaling in polyglutamine-triggered diseases.     

Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.     

TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to ～5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.     

Consensus supertrees: The synthesis of rooted trees containing overlapping sets of labeled leaves

Given two dendrograms (rooted tree diagrams) which have some but not all of their base points in common, a supertree is a dendrogram from which each of the original trees can be regarded as samples The distinction is made between inconsistent and consistent sample trees, defined by whether or not the samples provide contradictory information about the supertree An algorithm for obtaining the strict consensus supertree of two consistent sample trees is presented, as are procedures for merging two inconsistent sample trees Some suggestions for future work are made