Glycan Evolution in Response to Collaboration,Conflict, and Constraint

Glycans, oligo- and polysaccharides secreted or attached to proteins and lipids, cover the surfaces of all cells and have a regulatory capacity and structural diversity beyond any other class of biological molecule. Glycans may have evolved these properties because they mediate cellular interactions and often face pressure to evolve new functions rapidly. We approach this idea two ways. First, we discuss evolutionary innovation. Glycan synthesis, regulation, and mode of chemical interaction influence the spectrum of new forms presented to evolution. Second, we describe the evolutionary conflicts that arise when alleles and individuals interact. Glycan regulation and diversity are integral to these biological negotiations. Glycans are tasked with such an amazing diversity of functions that no study of cellular interaction can begin without considering them. We propose that glycans predominate the cell surface because their physical and chemical properties allow the rapid innovation required of molecules on the frontlines of evolutionary conflict.     

Substrate specificity and acute regulation of the tumour suppressor phosphatase, PTEN

PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumour suppressor that functions as a PtdIns(3,4,5)P3 3-phosphatase to inhibit cell proliferation, survival and growth by antagonizing PI3K (phosphoinositide 3-kinase)-dependent signalling. Recent work has begun to focus attention on potential biological functions of the protein phosphatase activity of PTEN and on the possibility that some of its functions are phosphatase-independent. We discuss here the structural and regulatory mechanisms that account for the remarkable specificity of PTEN with respect to its PtdIns substrates and how it avoids the soluble headgroups of PtdIns that occur commonly in cells. Secondly we discuss the concept of PTEN as a constitutively active enzyme that is subject to negative regulation both physiologically and pathologically. Thirdly, we review the evidence that PTEN functions as a dual specificity phosphatase with discrete lipid and protein substrates. Lastly we present a current model of how PTEN may participate in the control of cell migration.     

Perturbation of biological processes with small molecule kinase inhibitors

The reversible phosphorylation of substrates mediated by kinases and phosphatases affects their subcellular localization, catalytic activity, and/or interaction with other molecules. It is essential for signal transduction and the regulation of nearly all cellular processes, such as proliferation, apoptosis, metabolism, motility, and differentiation. Small molecule kinase inhibitors (SMKIs) have served as critical chemical probes to reveal the biological functions and mechanisms of kinases and their potential as therapeutic targets. In this review, we focused on a few novel SMKIs and their recent application in biological and preclinical studies to showcase how highly selective and potent SMKIs can be developed and utilized to propel the investigations on kinases and the biology behind.     

Yeast ABC transporters-- a tale of sex, stress, drugs and aging

Yeast ATP-binding cassette (ABC) proteins are implicated in many biological phenomena, often acting at crossroads of vital cellular processes. Their functions encompass peptide pheromone secretion, regulation of mitochondrial function, vacuolar detoxification, as well as pleiotropic drug resistance and stress adaptation. Because yeast harbors several homologues of mammalian ABC proteins with medical importance, understanding their molecular mechanisms, substrate interaction and three-dimensional structure of yeast ABC proteins might help identifying new approaches aimed at combating drug resistance or other ABC-mediated diseases. This review provides a comprehensive discussion on the functions of the ABC protein family in the yeast Saccharomyces cerevisiae.     

Mitochondrial sirtuins,metabolism, and aging

Maintaining metabolic homeostasis is essential for cellular and organismal health throughout life. Multiple signaling pathways that regulate metabolism also play critical roles in aging, such as PI3K/AKT, mTOR, AMPK, and sirtuins (SIRTs). Among them, sirtuins are known as a protein family with versatile functions, such as metabolic control, epigenetic modification and lifespan extension. Therefore, by understanding how sirtuins regulate metabolic processes, we can start to understand how they slow down or accelerate biological aging from the perspectives of metabolic regulation. Here, we review the biology of SIRT3, SIRT4, and SIRT5, known as the mitochondrial sirtuins due to their localization in the mitochondrial matrix. First, we will discuss canonical pathways that regulate metabolism more broadly and how these are integrated with aging regulation. Then, we will summarize the current knowledge about functional differences between SIRT3, SIRT4, and SIRT5 in metabolic control and integration in signaling networks. Finally, we will discuss how mitochondrial sirtuins regulate processes associated with aging and aging-related diseases.     

Sarcolectin (SCL): structure and expression of the recombinant molecule.

Interferons (IFNs) are major cytokines, responsible for down-regulating cell growth and for promoting cell differentiation. The sarcolectin (SCL) protein presented here blocks in the cells the established IFN-dependent interphase and stimulates DNA synthesis, probably in co-ordination with more specific growth factors or hormones. The SCL-DNA structure is closely related to that of cytokeratine K2C7 intermediate filaments, but the SCL is a monomer, or sometimes a dimer, which is excreted into the serum, where it is frequently bound to albumin. Its specific biological functions are carried by the beta sheets, and can be found on the two terminal domains of the molecule, the lectinic properties being located mainly on the N-terminus. The recombinant SCL molecule possesses the same biological functions as the native one, since it inhibits the IFN-dependent antiviral state both in human and in mouse cell cultures. On the contrary, antibodies raised against amino acids 41-55 located on the N-terminal domain of SCL inhibit this antagonistic effect. We postulate that the IFN and SCL proteins, because of their opposite biological functions, are in balance and are part of a feedback system operating the regulation of normal growth. In pathological cases, SCL could play a role in the development of tumors, as we have found in juvenile osteosarcomas or in AIDS cases.     

Say NO to neurodegeneration: role of S-nitrosylation in neurodegenerative disorders

Nitric oxide (NO) is an important signaling molecule that controls a wide range of biological processes. One of the signaling mechanisms of NO is through the S-nitrosylation of cysteine residues on proteins. S-nitrosylation is now regarded as an important redox signaling mechanism in the regulation of different cellular and physiological functions. However, deregulation of S-nitrosylation has also been linked to various human diseases such as neurodegenerative disorders. Nitrosative stress has long been considered as a major mediator in the development of neurodegeneration, but the molecular mechanism of how NO can contribute to neurodegeneration is not completely clear. Early studies suggested that nitration of proteins, which can induce protein aggregation might contribute to the neurodegenerative process. However, several recent studies suggest that S-nitrosylation of proteins that are important for neuronal survival contributes substantially in the development of various neurodegenerative disorders. Thus, in-depth understanding of the mechanism of neurodegeneration in relation to S-nitrosylation will be critical for the development of therapeutic treatment against these neurodegenerative diseases.     

Bone morphogenetic protein-15. Identification of target cells and biological functions

In developing ovarian follicles, the regulation of cell proliferation and differentiation is tightly coordinated. Precisely how this coordination is achieved is unknown, but recent observations have suggested that molecules emitted by the oocyte are involved in the process. The newly discovered oocyte-specific growth factor, bone morphogenetic protein-15 (BMP-15), is one such molecule. At present, nothing is known about the target cells and biological functions of BMP-15. To fill this gap in our knowledge, recombinant BMP-15 and its antibody were produced and used to determine BMP-15 expression and bioactivity. BMP-15 mRNA and protein were shown to be co-expressed in oocytes throughout folliculogenesis, supporting the idea that BMP-15 is a physiological regulator of follicle cell proliferation and/or differentiation. To test this, we used primary cultures of rat granulosa cells (GCs). We found that BMP-15 is a potent stimulator of GC proliferation, and importantly, the mitogenic effect was follicle-stimulating hormone (FSH)-independent. By contrast, BMP-15 alone had no effect on steroidogenesis. However, it produced a marked decrease in FSH-induced progesterone production, but had no effect on FSH-stimulated estradiol production. This result indicates that BMP-15 is a selective modulator of FSH action. In summary, this study identifies GCs as the first target cells for BMP-15. Moreover, it identifies the stimulation of GC proliferation and the differential regulation of two crucial steroid hormones as the first biological functions of BMP-15. Significantly, BMP-15 is the first growth factor that can coordinate GC proliferation and differentiation in a way that reflects normal physiology.     

The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness,sexual selection and fitness

Melatonin is a molecule present in a multitude of taxa and may be ubiquitous in organisms. It has been found in bacteria, unicellular eukaryotes, macroalgae, fungi, plants and animals. A primary biological function of melatonin in primitive unicellular organisms is in antioxidant defence to protect against toxic free radical damage. During evolution, melatonin has been adopted by multicellular organisms to perform many other biological functions. These functions likely include the chemical expression of darkness in vertebrates, environmental tolerance in fungi and plants, sexual signaling in birds and fish, seasonal reproductive regulation in photoperiodic mammals, and immunomodulation and anti‐inflammatory activity in all vertebrates tested. Moreover, its waning production during aging may indicate senescence in terms of a bio‐clock in many organisms. Conversely, high melatonin levels can serve as a signal of vitality and health. The multiple biological functions of melatonin can partially be attributed to its unconventional metabolism which is comprised of multi‐enzymatic, pseudo‐enzymatic and non‐enzymatic pathways. As a result, several bioactive metabolites of melatonin are formed during its metabolism and some of the presumed biological functions of melatonin reported to date may, in fact, be mediated by these metabolites. The changing biological roles of melatonin seem to have evolved from its primary function as an antioxidant.     

HIF-NOS信号通路对哺乳动物卵巢NO依赖性功能的调控作用

一氧化氮(NO)作为气体明星分子和信号分子,在哺乳动物体内不同的生理调节过程中具有非常重要的作用,尤其是哺乳动物卵巢功能的调控.一氧化氮合酶(NOS)是NO合成的限速酶,是调节NO合成的关键环节,也是NO依赖性功能调控的重要环节.因此,调节NOS转录/合成的信号通路对哺乳动物卵巢NO依赖性功能具有至关重要的调控作用.最近的研究发现,缺氧诱导因子(HIF)作为转录因子,参与许多与缺氧相关靶基因的转录调控,如NOS和血管内皮生长因子(VEGF)等.本文一方面描述了NO合成及其调控的分子机制,另一方面阐明了HIF作为转录因子对NOS的转录调控,从而揭示HIF在NO依赖性卵巢功能调控中的重要作用,同时为进一步研究哺乳动物卵巢功能的调控提供新的研究方向和理论基础.     

The human beta-defensin-3, an antibacterial peptide with multiple biological functions

A group of interesting molecules called defensins exhibit multiple functions but have been primarily recognized to possess a broad spectrum of antimicrobial activities. Studies have reported two different types of defensins (α and β) from human and animals, a cyclic θ defensin from rhesus, and several defensin-like peptides from plants. There is no amino acid sequence homology between these peptides, but they all contain three Cys-Cys disulfide linkages while the connectivities are different. Human β-defensin-3 (HβD-3) is the most recently discovered member of the host-defense peptide family that has attracted much attention. This molecule is expressed either constitutively or induced upon a challenge, and a growing evidence indicates the involvement of such molecules in adaptive immunity as well. It has been shown to exhibit antibacterial activities towards Gram-negative and Gram-positive bacteria as well as an ability to act as a chemo-attractant. Analysis of NMR structural data suggested a symmetrical dimeric form of this peptide in solution, which consists of three β strands and a short helix in the N-terminal region. While the disulfide linkages are known to provide the structural stability and stability against proteases, the biological relevance of this dimeric form was contradicted by another biological study. Since there is considerable current interest in developing HβD-3 for possible pharmaceutical applications, studies to further our understanding on the determinants of antibacterial activities and immunomodulatory function of HβD-3 are considered to be highly significant. The knowledge of its biosynthetic regulation will also help in understanding the role of HβD-3 in immunity. This article presents an overview of the expression and regulation of HβD-3 in humans, and the structure-function correlations among HβD-3 and its modified peptides are discussed emphasizing the functional importance. The future scope for studies on HβD-3 and design of short potent antimicrobial peptides, based on the native HβD-3 molecule, that do not interfere in the immunomodulatory function is also outlined.     

The human beta-defensin-3, an antibacterial peptide with multiple biological functions

A group of interesting molecules called defensins exhibit multiple functions but have been primarily recognized to possess a broad spectrum of antimicrobial activities. Studies have reported two different types of defensins (alpha and beta) from human and animals, a cyclic theta defensin from rhesus, and several defensin-like peptides from plants. There is no amino acid sequence homology between these peptides, but they all contain three Cys-Cys disulfide linkages while the connectivities are different. Human beta-defensin-3 (HbetaD-3) is the most recently discovered member of the host-defense peptide family that has attracted much attention. This molecule is expressed either constitutively or induced upon a challenge, and a growing evidence indicates the involvement of such molecules in adaptive immunity as well. It has been shown to exhibit antibacterial activities towards Gram-negative and Gram-positive bacteria as well as an ability to act as a chemo-attractant. Analysis of NMR structural data suggested a symmetrical dimeric form of this peptide in solution, which consists of three beta strands and a short helix in the N-terminal region. While the disulfide linkages are known to provide the structural stability and stability against proteases, the biological relevance of this dimeric form was contradicted by another biological study. Since there is considerable current interest in developing HbetaD-3 for possible pharmaceutical applications, studies to further our understanding on the determinants of antibacterial activities and immunomodulatory function of HbetaD-3 are considered to be highly significant. The knowledge of its biosynthetic regulation will also help in understanding the role of HbetaD-3 in immunity. This article presents an overview of the expression and regulation of HbetaD-3 in humans, and the structure-function correlations among HbetaD-3 and its modified peptides are discussed emphasizing the functional importance. The future scope for studies on HbetaD-3 and design of short potent antimicrobial peptides, based on the native HbetaD-3 molecule, that do not interfere in the immunomodulatory function is also outlined.     

长链非编码RNA与表观遗传调控

近年来,表观遗传学(epigenetics)备受关注.表观遗传调控的方式主要包括DNA甲基化、组蛋白修饰和染色质重塑等.ENCODE计划及随后的研究发现,人类基因组中仅有很小一部分DNA序列负责编码蛋白质,而其余大部分被转录为非编码RNA(non-codingRNA,ncRNA).其中长链非编码RNA(long non-codingRNA,lncRNA)是一类长度大于200nt并且缺乏蛋白质编码能力的RNA分子.越来越多的研究表明,lncRNAs能够通过表观遗传调控、转录调控以及转录后调控等多个层面调节基因的表达,从而参与细胞增殖、分化和凋亡等多种生物学过程.本文将着重综述lncRNAs在表观遗传调控中的作用及其最新的研究进展.     

Mapping CD55 function. The structure of two pathogen-binding domains at 1.7 A

Decay-accelerating factor (CD55), a regulator of the alternative and classical pathways of complement activation, is expressed on all serum-exposed cells. It is used by pathogens, including many enteroviruses and uropathogenic Escherichia coli, as a receptor prior to infection. We describe the x-ray structure of a pathogen-binding fragment of human CD55 at 1.7 A resolution containing two of the three domains required for regulation of human complement. We have used mutagenesis to map biological functions onto the molecule; decay-accelerating activity maps to a single face of the molecule, whereas bacterial and viral pathogens recognize a variety of different sites on CD55.     

Understanding atomic bonding and electronic distributions of a DNA molecule using DFT calculation and BOLS-BC model

Deoxyribonucleic acid (DNA) is an important molecule that has been extensively researched, mainly due to its structure and function. Herein, we investigated the electronic behavior of the DNA molecule containing 1008 atoms using density functional theory. The bond-charge (BC) model shows the relationship between charge density and atomic strain. Besides, the model mentioned above is combined with the bond-order-length-strength (BOLS) notion to calculate the atomic cohesive energy, the bond energy, and the local bond strain of the DNA chain. Using the BOLS-BC model, we were able to obtain information on the bonding features of the DNA chain and better comprehend the associated properties of electrons in biological systems. Consequently, this report functions as a theoretical reference for the precise regulation of the electrons and the bonding states of biological systems.