1,721,034 research outputs found
Control of human VDAC-2 scaffold dynamics by interfacial tryptophans is position specific
No full textAbstractMembrane proteins employ specific distribution patterns of amino acids in their tertiary structure for adaptation to their unique bilayer environment. The solvent-bilayer interface, in particular, displays the characteristic ‘aromatic belt’ that defines the transmembrane region of the protein, and satisfies the amphipathic interfacial environment. Tryptophan—the key residue of this aromatic belt—is known to influence the folding efficiency and stability of a large number of well-studied α-helical and β-barrel membrane proteins. Here, we have used functional and biophysical techniques coupled with simulations, to decipher the contribution of strategically placed four intrinsic tryptophans of the human outer mitochondrial membrane protein, voltage-dependent anion channel isoform-2 (VDAC-2). We show that tryptophans help in maintaining the structural and functional integrity of folded hVDAC-2 barrel in micellar environments. The voltage gating characteristics of hVDAC-2 are affected upon mutation of tryptophans at positions 75, 86 and 221. We observe that Trp-160 and Trp-221 play a crucial role in the folding pathway of the barrel, and once folded, Trp-221 helps stabilize the folded protein in concert with Trp-75 and Trp-160. We further demonstrate that substituting Trp-86 with phenylalanine leads to the formation of stable barrel. We find that the region comprising strand β4 (Trp-86) and β10-14 (Trp-160 and Trp-221) display slower and faster folding kinetics, respectively, providing insight into a possible directional folding of hVDAC-2 from the C-terminus to N-terminus. Our results show that residue selection in a protein during evolution is a balancing compromise between optimum stability, function, and regulating protein turnover inside the cell
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Aromatic interactions in β-hairpin scaffold stability: A historical perspective
No full textNon-covalent interactions between naturally occurring aromatic residues have been widely exploited as scaffold stabilizing agents in de novo designed peptides and in Nature – inspired structures. Our understanding of the factors driving aromatic interactions and their observed interaction geometries have advanced remarkably with improvements in conventional structural studies, availability of novel molecular methods and in silico studies, which have together provided atomistic information on aromatic interactions and interaction strengths. This review attempts to recapitulate the early advances in our understanding of aromatic interactions as stabilizing agents of peptide β-hairpins
Thermodynamic partitioning forces at the membrane protein interface
No full textTransmembrane proteins fold by the orchestrated interplay of membrane chaperones, holdases and the lipid membrane. Upon folding, membrane protein systems attain a thermodynamically stabilized framework through optimized energetics involving protein – membrane – solvent interactions. In particular, the water-bilayer interface demands selectively positioned amino acids to arbitrate interactions between the hydrophobic interior and polar phospholipid headgroups. A fundamental question that arises is the extent to which the amino acid side chain contributes to membrane protein folding and in maintaining protein-lipid interactions at the intricate interface environment of membrane proteins. Our goal is to experimentally deduce the partitioning cost of amino acids at the interface, and the associated physical principles governing the overall scaffold stability.
Interface residues are important contributors for membrane protein folding, and additionally serve as post-folding membrane anchors. In this study, we have quantified the free energy change associated with the chemical nature of the residue at the membrane interface. We achieve this by studying the unassisted folding equilibrium of the 8-stranded transmembrane β-barrel enzyme PagP in phosphocholine lipidic micelles and lipid vesicles. We present the first experimentally measured whole-protein free energy scale for side chain partitioning at the membrane interface, for all naturally abundant amino acids. We obtain differential contributions of the protein- and lipid-facing interface residues to the barrel folding pathway and stability of the folded scaffold. The most favorable transfer at the amphiphilic lipid-facing interface is for hydrophobic amino acids, whereas we observe the highest energetic cost of transfer for charged and polar groups. On the contrary, we find that small and polar residues are most favorably transferred to the protein-facing interface, whereas hydrophobic and aromatic residues promote alternate folding pathways in PagP.
Our studies establish that the side chain non-polar accessible surface area shows a direct correlation with the partitioning free energy change at the lipid-facing interface residue. We also find that the non-polar accessible surface correlates inversely with the thermodynamic partitioning free energy change when the interface residue is protein-facing. We demonstrate how PagP maintains a balance between concerted folding and hydrophobic collapse by evolutionary choice of small polar residues at the protein-facing interface. We also identify the importance of interface polar residues to the folding pathway of β-barrel membrane proteins
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Oxidative Thiol Modifications as Molecular Redox Sensors in Human Mitochondria
No full textNeurodegenerative diseases and ageing are intricately linked with biological cellular levels of reactive oxygen species (ROS). The highest levels of ROS are produced during mitochondrial respiration, and an optimal balance of ROS levels for physiological signaling over cellular damage is regulated by ROS scavengers. In the mitochondrial outer membrane, voltage-dependent anion channels (VDACs) are believed to function in close conjunction with the molecular ROS sensors in the mitochondrial intermembrane space, to balance ROS transport into the cytosolic milieu versus the trigger of mitochondria-mediated apoptosis. However, the role of mitochondrial VDACs, and the molecular elements involved in ROS scavenging, has not yet been identified. In particular, the anti-apoptotic function of human VDAC2 isoform and the unusual abundance of thiolate ions - ¬presented as cysteines in VDAC2 - allowed us to hypothesize that redox homeostasis is effected by VDAC2 cysteines. Using molecular measurements of VDAC2 energetics in native-like environments, single-channel functional studies and insights from oxidative cysteine modifications in vitro and in vivo, we demonstrate that VDAC2 has evolutionary role as a molecular redox regulator. Cysteine enrichment in human VDAC2 is not stochastic, and is essential to counter cellular oxidative challenges and redox stress. For the first time in mitochondrial bioenergetics, our findings demonstrate both a vital role of VDAC2 as a metabolite flux regulator and how this protein is indispensable for oxidative homeostasis and the trigger of mitophagy
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