Molecular docking analysis of hyperphosphorylated tau protein with compounds derived from Bacopa monnieri and Withania somnifera

Tau protein, the major player in Alzheimer’s disease forms neurofibrillary tangles in elderly people. Bramhi (Baccopa Monniera) is often used as an ayurvedic treatment for Alzheimer''s disease. Therefore it is of interest to study the interaction of compounds derived from Baccopa with the Tau protein involved in tangle formation. We show that compounds such as bacopaside II, bacopaside XII, and nicotine showed optimal binding features with the R2 repeat domain of hyperphosphorylated tau protein for further consideration in the context of Alzheimer''s disease (AD).     

Dimeric assembly of human Suv3 helicase promotes its RNA unwinding function in mitochondrial RNA degradosome for RNA decay

Human Suv3 is a unique homodimeric helicase that constitutes the major component of the mitochondrial degradosome to work cooperatively with exoribonuclease PNPase for efficient RNA decay. However, the molecular mechanism of how Suv3 is assembled into a homodimer to unwind RNA remains elusive. Here, we show that dimeric Suv3 preferentially binds to and unwinds DNA–DNA, DNA–RNA, and RNA–RNA duplexes with a long 3′ overhang (≥10 nucleotides). The C‐terminal tail (CTT)‐truncated Suv3 (Suv3ΔC) becomes a monomeric protein that binds to and unwinds duplex substrates with ~six to sevenfold lower activities relative to dimeric Suv3. Only dimeric Suv3, but not monomeric Suv3ΔC, binds RNA independently of ATP or ADP, and is capable of interacting with PNPase, indicating that dimeric Suv3 assembly ensures its continuous association with RNA and PNPase during ATP hydrolysis cycles for efficient RNA degradation. We further determined the crystal structure of the apo‐form of Suv3ΔC, and SAXS structures of dimeric Suv3 and PNPase–Suv3 complex, showing that dimeric Suv3 caps on the top of PNPase via interactions with S1 domains, and forms a dumbbell‐shaped degradosome complex with PNPase. Overall, this study reveals that Suv3 is assembled into a dimeric helicase by its CTT for efficient and persistent RNA binding and unwinding to facilitate interactions with PNPase, promote RNA degradation, and maintain mitochondrial genome integrity and homeostasis.     

Anti-HIV drugs: comparative toxicities in murine fetal liver and bone marrow erythroid progenitor cells

The toxicity of anti-HIV drugs, 3'-azido-3'-deoxythymidine (zidovudine, AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxy-2',3'-didehydrothymidine (d4T) and ribavirin was studied in vitro in murine fetal liver cells (FLC) and in bone marrow cells. These studies indicate that d4T is the least toxic drug and ribavirin is the most toxic agent in both models. However, the murine FLC system was found to be a more sensitive model for the assessment of toxicity of anti-HIV agents towards erythroid progenitor cells as indicated by the IC50 values.     

p27Kip1 regulates T cell proliferation

Our studies addressed the mechanism by which serum acts in conjunction with T cell receptor (TCR) agonists to promote the proliferation of primary splenic T cells. When added to resting splenocytes, TCR agonists initiated G(0)/G(1) traverse and activated cyclin D3-cdk6 complexes in a serum-independent manner. On the other hand, both TCR agonists and 10% serum were required for the activation of cyclin E-cdk2 and cyclin A-cdk2 complexes and the entry of cells into S phase. Serum facilitated cdk2 activation by maximizing the extent and extending the duration of the TCR-initiated down-regulation of the cdk2 inhibitor, p27(Kip1). Although p27(Kip1) levels were reduced (albeit submaximally) in cells stimulated in serum-deficient medium, nearly all of the cdk2 complexes in these cells contained p27(Kip1). In contrast, in cells receiving TCR agonist and 10% serum, little if any p27(Kip1) was present in cyclin-cdk2 complexes. Unlike wild-type splenocytes, p27(Kip1)-null splenocytes did not require serum for cdk2 activation or S phase entry whereas loss of the related cdk2 inhibitor, p21(Cip1), did not override the serum dependence of these responses. We also found that cdk2 activation was both necessary and sufficient for maximal expression of cdk2 protein. These studies provide a mechanistic basis for the serum dependence of T cell mitogenesis.     

Possible consequences of genes of major effect: transient changes in the G-matrix

Understanding the process of evolutionary divergence requires knowledge of the strength, form, and targets of selection, as well as the genetic architecture of the divergent traits. Quantitative genetic approaches to understanding multivariate selection and genetic response to selection have proven to be powerful tools in this endeavor, particularly with respect to short-term evolution. However, the application of quantitative genetic theory over periods of substantial phenotypic change is controversial because it requires that the requisite genetic parameters remain constant over the period of time in question. We show herein how attempts to determine the stability of key genetic parameters may be misled by the many genes of small effect type of genetic architecture generally assumed in quantitative genetics. The presence of genes of major effect (GOMEs) can alter the genetic variance-covariance matrix dramatically for brief periods of time, significantly alter the rate and trajectory of multivariate evolution, and thereby mislead attempts to reconstruct or predict long term evolution.     

On indirect genetic effects in structured populations

Indirect genetic effects (IGEs) occur when the phenotype of an individual, and possibly its fitness, depends, at least in part, on the genes of its social partners. The effective result is that environmental sources of phenotypic variance can themselves evolve. Simple models have shown that IGEs can alter the rate and direction of evolution for traits involved in interactions. Here we expand the applicability of the theory of IGEs to evolution in metapopulations by including nonlinear interactions between individuals and population genetic structure. Although population subdivision alone generates some dramatic and nonintuitive evolutionary dynamics for interacting phenotypes, the combination of nonlinear interactions with subdivision reveals an even greater importance of IGEs. The presence of genetic structure links the evolution of interacting phenotypes and the traits that influence their expression ("effector traits") even in the absence of genetic correlations. When nonlinear social effects occur in subdivided populations, evolutionary response is altered and can even oppose the direction expected due to direct selection. Because population genetic structure allows for multilevel selection, we also investigate the role of IGEs in determining the response to individual and group selection. We find that nonlinear social effects can cause interference between levels of selection even when they act in the same direction. In some cases, interference can be so extreme that the actual evolutionary response to multilevel selection is opposite in direction to that predicted by summing selection at each level. This theoretical result confirms empirical data that show higher levels of selection cannot be ignored even when selection acts in the same direction at all levels.     

Topology and structure of the C1q-binding site on C-reactive protein

The host defense functions of human C-reactive protein (CRP) depend to a great extent on its ability to activate the classical complement pathway. The aim of this study was to define the topology and structure of the CRP site that binds C1q, the recognition protein of the classical pathway. We have previously reported that residue Asp(112) of CRP plays a major role in the formation of the C1q-binding site, while the neighboring Lys(114) hinders C1q binding. The three-dimensional structure of CRP shows the presence of a deep, extended cleft in each protomer on the face of the pentamer opposite that containing the phosphocholine-binding sites. Asp(112) is part of this marked cleft that is deep at its origin but becomes wider and shallower close to the inner edge of the protomer and the central pore of the pentamer. The shallow end of the pocket is bounded by the 112-114 loop, residues 86-92 (the inner loop), the C terminus of the protomer, and the C terminus of the pentraxin alpha-helix 169-176, particularly Tyr(175). Mutational analysis of residues participating in the formation of this pocket demonstrates that Asp(112) and Tyr(175) are important contact residues for C1q binding, that Glu(88) influences the conformational change in C1q necessary for complement activation, and that Asn(158) and His(38) probably contribute to the correct geometry of the binding site. Thus, it appears that the pocket at the open end of the cleft is the C1q-binding site of CRP.     

Animation of the dynamical events of the elongation cycle based on cryoelectron microscopy of functional complexes of the ribosome

Using three-dimensional cryoelectron microscopy, the binding positions of tRNA and elongation factors EF-G and EF-Tu (the latter complexed with aminoacyl tRNA and GTP) on the ribosome were determined in previous studies. On the basis of these studies, the dynamical events that take place in the course of the elongation cycle of protein synthesis have been animated. The resulting 3-min movie is accessible on the website of this journal (http://www. idealibrary.com). The following article provides a brief annotation of those frames of the movie for which experimental support is available.     

Conformational variability in Escherichia coli 70S ribosome as revealed by 3D cryo-electron microscopy

During protein biosynthesis, ribosomes are believed to go through a cycle of conformational transitions. We have identified some of the most variable regions of the E. coli 70S ribosome and its subunits, by means of cryo-electron microscopy and three-dimensional (3D) reconstruction. Conformational changes in the smaller 30S subunit are mainly associated with the functionally important domains of the subunit, such as the neck and the platform, as seen by comparison of heat-activated, non-activated and 50S-bound states. In the larger 50S subunit the most variable regions are the L7/L12 stalk, central protuberance and the L1-protein, as observed in various tRNA-70S ribosome complexes. Difference maps calculated between 3D maps of ribosomes help pinpoint the location of ribosomal regions that are most strongly affected by conformational transitions. These results throw direct light on the dynamic behavior of the ribosome and help in understanding the role of these flexible domains in the translation process.     

Effect of buffer conditions on the position of tRNA on the 70 S ribosome as visualized by cryoelectron microscopy

The effect of buffer conditions on the binding position of tRNA on the Escherichia coli 70 S ribosome have been studied by means of three-dimensional (3D) cryoelectron microscopy. Either deacylated tRNAfMet or fMet-tRNAfMet were bound to the 70 S ribosomes, which were programmed with a 46-nucleotide mRNA having AUG codon in the middle, under two different buffer conditions (conventional buffer: containing Tris and higher Mg2+ concentration [10-15 mM]; and polyamine buffer: containing Hepes, lower Mg2+ concentration [6 mM], and polyamines). Difference maps, obtained by subtracting 3D maps of naked control ribosome in the corresponding buffer from the 3D maps of tRNA.ribosome complexes, reveal the distinct locations of tRNA on the ribosome. The position of deacylated tRNAfMet depends on the buffer condition used, whereas that of fMet-tRNAfMet remains the same in both buffer conditions. The acylated tRNA binds in the classical P site, whereas deacylated tRNA binds mostly in an intermediate P/E position under the conventional buffer condition and mostly in the position corresponding to the classical P site, i. e. in the P/P state, under the polyamine buffer conditions.