N-myristoylated proteins, key components in intracellular signal transduction systems enabling rapid and flexible cell responses

N-myristoylation, one of the co- or post-translational modifications of proteins, has so far been regarded as necessary for anchoring of proteins to membranes. Recently, we have revealed that Nα-myristoylation of several brain proteins unambiguously regulates certain protein–protein interactions that may affect signaling pathways in brain. Comparison of the amino acid sequences of myristoylated proteins including those in other organs suggests that this regulation is involved in signaling pathways not only in brain but also in other organs. Thus, it has been shown that myristoylated proteins in cells regulate the signal transduction between membranes and cytoplasmic fractions. An algorithm we have developed to identify myristoylated proteins in cells predicts the presence of hundreds of myristoylated proteins. Interestingly, a large portion of the myristoylated proteins thought to take part in signal transduction between membranes and cytoplasmic fractions are included in the predicted myristoylated proteins. If the proteins functionally regulated by myristoylation, a posttranslational protein modification, were understood as cross-talk points within the intracellular signal transduction system, known signaling pathways could thus be linked to each other, and a novel map of this intracellular network could be constructed. On the basis of our recent results, this review will highlight the multifunctional aspects of protein N-myristoylation in brain

Pro-Inflammatory S100A8 and S100A9 Proteins: Self-Assembly into Multifunctional Native and Amyloid Complexes

S100A8 and S100A9 are EF-hand Ca2+ binding proteins belonging to the S100 family. They are abundant in cytosol of phagocytes and play critical roles in numerous cellular processes such as motility and danger signaling by interacting and modulating the activity of target proteins. S100A8 and S100A9 expression levels increased in many types of cancer, neurodegenerative disorders, inflammatory and autoimmune diseases and they are implicated in the numerous disease pathologies. The Ca2+ and Zn2+-binding properties of S100A8/A9 have a pivotal influence on their conformation and oligomerization state, including self-assembly into homo- and heterodimers, tetramers and larger oligomers. Here we review how the unique chemical and conformational properties of individual proteins and their structural plasticity at the quaternary level account for S100A8/A9 functional diversity. Additional functional diversification occurs via non-covalent assembly into oligomeric and fibrillar amyloid complexes discovered in the aging prostate and reproduced in vitro. This process is also regulated by Ca2+and Zn2+-binding and effectively competes with the formation of the native complexes. High intrinsic amyloid-forming capacity of S100A8/A9 proteins may lead to their amyloid depositions in numerous ailments characterized by their elevated expression patterns and have additional pathological significance requiring further thorough investigation

The accuracy of the orifice in measuring small flows of gas

Call number: LD2668 .T4 1934 V4

Identification of Regions Responsible for the Open Conformation of S100A10 Using Chimaeric S100A11-S100A10 Proteins

S100A11 is a dimeric EF-hand calcium-binding protein. Calcium binding to S100A11 results in a large conformational change that uncovers a broad hydrophobic surface used to interact with phospholipid-binding proteins (annexins A1 and A2) and facilitate membrane vesiculation events. In contrast with other S100 proteins, S100A10 is unable to bind calcium due to deletion and substitution of calcium-ligating residues. Despite this, calcium-free S100A10 assumes an \u27open\u27 conformation that is very similar to S100A11 in its calcium-bound state. To understand how S100A10 is able to adopt an open conformation in the absence of calcium, seven chimaeric proteins were constructed where regions from calcium-binding sites I and II, and helices II-IV in S100A11 were replaced with the corresponding regions of S100A10. The chimaeric proteins having substitutions in calcium-binding site II displayed increased hydrophobic surface exposure as assessed by bis-ANS (4,4\u27-dianilino-1,1\u27-binaphthyl-5,5\u27disulfonic acid, dipotassium salt) fluorescence and phenyl-Sepharose binding in the absence of calcium. This response is similar to that observed for Ca2+-S100A11 and calcium-free S100A10. Further, this substitution resulted in calcium-insensitive binding to annexin A2 for one chimaeric protein. The results indicate that residues within site II are important in stabilizing the open conformation of S100A10 and presentation of its target binding site. In contrast, S100A11 chimaeric proteins with helical substitutions displayed poorer hydrophobic surface exposure and, consequently, unobservable annexin A2 binding. The present study represents a first attempt to systematically understand the molecular basis for the calcium-insensitive open conformation of S100A10

Arabinoxylan supplemented bread : From extraction of fibers to effect of baking, digestion, and fermentation

The intake of dietary fibers is related with important benefits for human health. We produced two different arabinoxylan fibers with (FAX) and without ferulic acid linked (AX), 12.5 and 0.1 mg g- 1 of ferulic acid respectively, by subcritical water extraction of wheat bran. Both FAX and AX fibers were used as supplement in bread production, while non-supplemented bread was used as control. Through an enzymatic deconstruction process we investigated the effect of bread making on the fibers, the preservation of their molecular structure (A/ X ratio of 0.13 and Mw of 105 Da) and the interaction with other macromolecules in the bread. By mimicking the upper track digestion, we could confirm the non-digestability of the fibers and we used them for the fermentation with B. ovatus and B. adolescentis. The presence of AX fibers during fermentation showed specific substrate adaptation by the probiotic bacteria in correlation with its potential prebiotic effect.Peer reviewe

A Combined Theoretical and Experimental Study of the Polymer Matrix-Mediated Stress Transfer in a Cellulose Nanocomposite

We study composites of cellulose nanocrystals (CNCs) in an ionomer matrix of poly(ethylene-stat-sodium acrylate) and find that direct cellulose/cellulose interactions in the composite are not a requirement for achieving reinforcement. While isotropic composites only show a slightly enhanced stiffness compared to the neat ionomer, a more substantial increase in Youngs modulus by a factor of up to 5 is achieved by uniaxial alignment of the composites through melt spinning. The orientation of CNC in melt-spun composites reduces the probability of cellulose/cellulose interactions, which suggests that cellulose/polymer interactions must be present that lead to the observed reinforcement. Molecular dynamics simulations confirm strong cellulose/polymer interactions in the form of ionic interactions as well as hydrogen bonding. These cellulose/polymer interactions facilitate efficient stress transfer, leading to the high reinforcing effect of CNC, while cellulose/cellulose interactions play a minor role in the mechanical response of the composite.Funding Agencies|Swedish Foundation for Strategic ResearchSwedish Foundation for Strategic Research [RMA15-0052]; Swedish Research Council FormasSwedish Research CouncilSwedish Research Council Formas [FR-2018/0010]; Treesearch; Chalmers University of Technology Foundation; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-06487 RFI NanoSPAM]</p

RG100204, A Novel Aquaporin-9 Inhibitor, Reduces Septic Cardiomyopathy and Multiple Organ Failure in Murine Sepsis

International audienceSepsis is caused by systemic infection and is a major health concern as it is the primary cause of death from infection. It is the leading cause of mortality worldwide and there are no specific effective treatments for sepsis. Gene deletion of the neutral solute channel Aquaporin 9 (AQP9) normalizes oxidative stress and improves survival in a bacterial endotoxin induced mouse model of sepsis. In this study we described the initial characterization and effects of a novel small molecule AQP9 inhibitor, RG100204, in a cecal ligation and puncture (CLP) induced model of polymicrobial infection. In vitro, RG100204 blocked mouse AQP9 H 2 O 2 permeability in an ectopic CHO cell expression system and abolished the LPS induced increase in superoxide anion and nitric oxide in FaO hepatoma cells. Pre-treatment of CLP-mice with RG100204 (25 mg/kg p.o. before CLP and then again at 8 h after CLP) attenuated the hypothermia, cardiac dysfunction (systolic and diastolic), renal dysfunction and hepatocellular injury caused by CLP-induced sepsis. Post-treatment of CLP-mice with RG100204 also attenuated the cardiac dysfunction (systolic and diastolic), the renal dysfunction caused by CLP-induced sepsis, but did not significantly reduce the liver injury or hypothermia. The most striking finding was that oral administration of RG100204 as late as 3 h after the onset of polymicrobial sepsis attenuated the cardiac and renal dysfunction caused by severe sepsis. Immunoblot quantification demonstrated that RG100204 reduced activation of the NLRP3 inflammasome pathway. Moreover, myeloperoxidase activity in RG100204 treated lung tissue was reduced. Together these results indicate that AQP9 may be a novel drug target in polymicrobial sepsis

Calcium Regulation of an Actin Spring

Calcium is essential for many biological processes involved in cellular motility. However, the pathway by which calcium influences motility, in processes such as muscle contraction and neuronal growth, is often indirect and complex. We establish a simple and direct mechanochemical link that shows how calcium quantitatively regulates the dynamics of a primitive motile system, the actin-based acrosomal bundle of horseshoe crab sperm. The extension of this bundle requires the continuous presence of external calcium. Furthermore, the extension rate increases with calcium concentration, but at a given concentration, we find that the volumetric rate of extension is constant. Our experiments and theory suggest that calcium sequentially binds to calmodulin molecules decorating the actin filaments. This binding leads to a collective wave of untwisting of the actin filaments that drives bundle extension