Biometals. 2010 Nov 19. [Epub ahead of print]
Conformational study of bovine lactoferricin in membrane-micking conditions by molecular dynamics simulation and circular dichroism.
Daidone I, Magliano A, Di Nola A, Mignogna G, Clarkson MM, Lizzi AR, Oratore A, Mazza F.
Department of Chemistry, Chemical Engineering and Materials, University of L'Aquila, via Vetoio (Coppito 1), 67010, Coppito, AQ, Italy.
Abstract
Lactoferricins are potent antimicrobial peptides released by pepsin cleavage of Lactoferrins. Bovine Lactoferricin (LfcinB) has higher activity than the intact bovine Lactoferrin, and is the most active among the other Lactoferricins of human, murine and caprine origin. In the intact protein the fragment corresponding to LfcinB is in an helical conformation, while in water LfcinB adopts an amphipathic β-hairpin structure. However, whether any of these structural motifs is the antibacterial active conformation, i.e., the one interacting with bacterial membrane components, remains to be seen. Here we present Circular Dichroism (CD) spectra and Molecular Dynamics (MD) simulations indicating that in membrane-mimicking solvents the LfcinB adopts an amphipathic β-hairpin structure similar to that observed in water, but differing in the dynamic behavior of the side-chains of the two tryptophan residues. In the membrane-mimicking solvent these side-chains show a high propensity to point towards the hydrophobic environment, rather than being in the hydrophobic core as seen in water, while the backbone preserves the hairpin conformation as found in water. These results suggest that the tryptophans might act as anchors pulling the stable, solvent-invariant hairpin structure into the membrane.
PMID: 21088870 [PubMed - as supplied by publisher]
Cell Mol Neurobiol. 2010 Nov 19. [Epub ahead of print]
Regulatory Peptides from Chromogranin A and Secretogranin II.
Department of Biomedicine, University of Bergen, Jonas Lies vei 91, 5009, Bergen, Norway, karen.helle@biomed.uib.no.
Abstract
This commentary is focusing on novel aspects on the secreted CgA- and SgII-derived peptides, vasostatin-I (bovine and human CgA(1-76), VS-I), WE-14 (CgA(316-329)), catestatin (bovine CgA(344-366), human CgA(352-372), Cts) and the SgII-derived secretoneurin (SgII(180-204)) as significant regulators of inflammatory reactions.
PMID: 21088887 [PubMed - as supplied by publisher]
Cell Mol Neurobiol. 2010 Nov 19. [Epub ahead of print]
Cytokine Interactions with Adrenal Medullary Chromaffin Cells.
Douglas SA, Sreenivasan D, Carman FH, Bunn SJ.
Department of Anatomy and Structural Biology, Centre for Neuroendocrinology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin, New Zealand.
Abstract
It is generally accepted that a bi-directional or reciprocal interaction occurs between the immune and neuroendocrine systems, and that this relationship is important for the appropriate physiological functioning of both systems. Similarly, an imbalance in this relationship may contribute to a number of pathologies, most notably those relating to stress. The aim of this article is to consider the interaction of cytokines with the adrenal medulla, a potentially important player in this relationship. The chromaffin cells of the adrenal medulla release catecholamines and a range of biologically active peptides in response to a wide variety of stress-related signals. A growing body of evidence indicates that this stress response is influenced by, and in turn has influence upon, immune signalling. This brief review will focus primarily on the best-described adrenal medullary active cytokines, namely interferon-α, interleukin-6, interleukin-1α/β and tumour necrosis factor-α. In each case, three key issues will be addressed: the physiologically relevant source of the cytokine; the intracellular signalling events arising from activation of its receptor and finally the cellular consequences of such activation in terms of modulation of gene expression and the secretory output of the chromaffin cells.
PMID: 21088883 [PubMed - as supplied by publisher]
Cell Tissue Res. 2010 Nov 19. [Epub ahead of print]
Biological roles of host defense peptides: lessons from transgenic animals and bioengineered tissues.
Dybvig T, Facci M, Gerdts V, Wilson HL.
Vaccine & Infectious Disease Organization (VIDO), University of Saskatchewan, 120 Veterinary Road, Saskatoon, Saskatchewan, S7N 5E3, Canada.
Abstract
Host defense peptides (HDPs) have long been recognized as microbicidal agents, but their roles as modulators of innate and adaptive immunity have only more recently been appreciated. The study of transgenic animal and tissue models has provided platforms to improve our understanding of the immune modulatory functions of HDPs. Here, the characterization of transgenic animals or tissue models that over-express and/or are deficient for specific HDPs is reviewed. We also attempt to reconcile this data with evidence from human studies monitoring HDP expression at constitutive levels and/or in conjunction with inflammation, infection models, or disease states. We have excluded activities ascribed to HDPs derived exclusively from in vitro experiments. An appreciation of the way that HDPs promote innate immunity or influence the adaptive immune response is necessary in order to exploit their therapeutic or adjuvant potential and to open new perspectives in understanding the basis of immunity. The potential applications for HDPs are discussed.
PMID: 21088855 [PubMed - as supplied by publisher]
Am J Pathol. 2010 Nov 18. [Epub ahead of print]
Transgenic Mice Overexpressing APP and Transforming Growth Factor-{beta}1 Feature Cognitive and Vascular Hallmarks of Alzheimer's Disease.
Ongali B, Nicolakakis N, Lecrux C, Aboulkassim T, Rosa-Neto P, Papadopoulos P, Tong XK, Hamel E.
From the Laboratory of Cerebrovascular Research,* and the Brain Imaging Centre, Montreal Neurological Institute, and Douglas Hospital Research Centre, McGill University, Montréal, Québec, Canada.
Abstract
High brain levels of amyloid-β (Aβ) and transforming growth factor-β1 (TGF-β1) have been implicated in the cognitive and cerebrovascular alterations of Alzheimer's disease (AD). We sought to investigate the impact of combined increases in Aβ and TGF-β1 on cerebrovascular, neuronal, and mnemonic function using transgenic mice overproducing these peptides (A/T mice). In particular, we measured cerebrovascular reactivity, evoked cerebral blood flow and glucose uptake during brain activation, cholinergic status, and spatial memory, along with cerebrovascular fibrosis, amyloidosis, and astrogliosis, and their evolution with age. An assessment of perfusion and metabolic responses was considered timely, given ongoing efforts for their validation as AD biomarkers. Relative to wild-type littermates, A/T mice displayed an early progressive decline in cerebrovascular dilatory ability, preserved contractility, and reduction in constitutive nitric oxide synthesis that establishes resting vessel tone. Altered levels of vasodilator-synthesizing enzymes and fibrotic proteins, resistance to antioxidant treatment, and unchanged levels of the antioxidant enzyme, superoxide dismutase-2, accompanied these impairments. A/T mice featured deficient neurovascular and neurometabolic coupling to whisker stimulation, cholinergic denervation, cerebral and cerebrovascular Aβ deposition, astrocyte activation, and impaired Morris water maze performance, which gained severity with age. The combined Aβ- and TGF-β1-driven pathology recapitulates salient cerebrovascular, neuronal, and cognitive AD landmarks and yields a versatile model toward highly anticipated diagnostic and therapeutic tools for patients featuring Aβ and TGF-β1 increments.
PMID: 21088218 [PubMed - as supplied by publisher]
Chem Soc Rev. 2010 Nov 18. [Epub ahead of print]
Nanoparticle-based mass spectrometry for the analysis of biomolecules.
Department of Chemistry, National Taiwan University, 1, Section 4, Roosevelt Road, Taipei 10617, Taiwan, R.O.C. changht@ntu.edu.tw.
Abstract
Nanoparticles (NPs) are useful as matrixes for the analyses of several types of biomolecules (including aminothiols, peptides, and proteins) and for mass spectrometric imaging through surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS), mainly because of their large surface area, strong absorption in the ultraviolet-near-infrared region, and ready functionalization. Metallic NPs, metal oxide NPs, and semiconductor quantum dots, unmodified or functionalized with recognition ligands, have a strong affinity toward analytes; therefore, they allow the enrichment of biomolecules, leading to improved sensitivity with minimal matrix interference in their mass spectra. SALDI-MS using NPs overcomes the two major problems commonly encountered in matrix-assisted laser desorption/ionization mass spectrometry: the presence of "sweet spots" and the high background signals in the low-mass region. In this tutorial review, we discuss the roles played by the nature, size, and concentration of the NPs, the buffer composition, and the laser energy in determining the sensitivity and mass ranges for the analytes. We describe internal standard SALDI-MS methods that allow the concentrations of analytes to be determined with low variation (relative standard deviations: <10%)>
PMID: 21088773 [PubMed - as supplied by publisher]
Org Biomol Chem. 2010 Nov 18. [Epub ahead of print]
Benzoylureas as removable cis amide inducers: synthesis of cyclic amides via ring closing metathesis (RCM).
Brady RM, Khakham Y, Lessene G, Baell JB.
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, Victoria, 3052, Australia. jbaell@wehi.edu.au glessene@wehi.edu.au.
Abstract
Rapid and high yielding synthesis of medium ring lactams was made possible through the use of a benzoylurea auxiliary that serves to stabilize a cisoid amide conformation, facilitating cyclization. The auxiliary is released after activation under the mild conditions required to deprotect a primary amine, such as acidolysis of a Boc group in the examples given here. This methodology is a promising tool for the synthesis of medium ring lactams, macrocyclic natural products and peptides.
PMID: 21088766 [PubMed - as supplied by publisher]
Proc Natl Acad Sci U S A. 2010 Nov 18. [Epub ahead of print]
Ca2+ signaling by plant Arabidopsis thaliana Pep peptides depends on AtPepR1, a receptor with guanylyl cyclase activity, and cGMP-activated Ca2+ channels.
Qi Z, Verma R, Gehring C, Yamaguchi Y, Zhao Y, Ryan CA, Berkowitz GA.
College of Life Science, Inner Mongolia University, Hohhot, Inner Mongolia 010021, China.
Abstract
A family of peptide signaling molecules (AtPeps) and their plasma membrane receptor AtPepR1 are known to act in pathogen-defense signaling cascades in plants. Little is currently known about the molecular mechanisms that link these signaling peptides and their receptor, a leucine-rich repeat receptor-like kinase, to downstream pathogen-defense responses. We identify some cellular activities of these molecules that provide the context for a model for their action in signaling cascades. AtPeps activate plasma membrane inwardly conducting Ca(2+) permeable channels in mesophyll cells, resulting in cytosolic Ca(2+) elevation. This activity is dependent on their receptor as well as a cyclic nucleotide-gated channel (CNGC2). We also show that the leucine-rich repeat receptor-like kinase receptor AtPepR1 has guanylyl cyclase activity, generating cGMP from GTP, and that cGMP can activate CNGC2-dependent cytosolic Ca(2+) elevation. AtPep-dependent expression of pathogen-defense genes (PDF1.2, MPK3, and WRKY33) is mediated by the Ca(2+) signaling pathway associated with AtPep peptides and their receptor. The work presented here indicates that extracellular AtPeps, which can act as danger-associated molecular patterns, signal by interaction with their receptor, AtPepR1, a plasma membrane protein that can generate cGMP. Downstream from AtPep and AtPepR1 in a signaling cascade, the cGMP-activated channel CNGC2 is involved in AtPep- and AtPepR1-dependent inward Ca(2+) conductance and resulting cytosolic Ca(2+) elevation. The signaling cascade initiated by AtPeps leads to expression of pathogen-defense genes in a Ca(2+)-dependent manner.
PMID: 21088220 [PubMed - as supplied by publisher]
Curr Opin Chem Biol. 2010 Nov 17. [Epub ahead of print]
Proteomic analysis of polyketide and nonribosomal peptide biosynthesis.
Department of Chemistry and Biochemistry, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0358, United States.
Abstract
Polyketides and non-ribosomal peptides are in a class of natural products important both as drug sources and as dangerous toxins and virulence factors. While studies over the last two decades have provided substantial characterization of the modular synthases that produce these compounds at the genetic level, their understanding at the protein level is much less understood. New proteomic platforms called an orthogonal active site identification system (OASIS) and proteomic interrogation of secondary metabolism (PrISM) have been developed to identify and quantify natural product synthase enzymes. Reviewed here, these tools offer the means to discover and analyze modular synthetic pathways that are limited by genetic techniques, opening the tools of contemporary proteomics to natural product sciences.
Copyright © 2010 Elsevier Ltd. All rights reserved.PMID: 21087894 [PubMed - as supplied by publisher]
Cell Cycle. 2010 Nov 15;9(22):4551-4559. [Epub ahead of print]
Stapled peptides in the p53 pathway: Computer simulations reveal novel interactions of the staples with the target protein.
Bioinformatics Institute; Matrix, Singapore.
Abstract
Atomistic simulations of a set of stapled peptides derived from the transactivation domain of p53 (designed by Verdine & colleagues, JACS 2007 129:2456) and complexed to MDM2 reveal that the good binders are uniquely characterized by higher helicity and by extensive interactions between the hydrocarbon staples and the MDM2 surface; in contrast the poor binders have reduced helicity and their staples are mostly solvent exposed. Our studies also find that the best binders can also potentially inhibit MDMX with similar affinities, suggesting that such stapled peptides can be evolved for dual inhibition with therapeutic potential.
PMID: 21088491 [PubMed - as supplied by publisher]
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