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Helix stabilization

Catarina S H Jesus, Pedro Fernandes Cruz, Luis G Arnaut, Rui M M Brito, Carlos Serpa
The understanding of fast folding dynamics of single α-helices comes mostly from studies on rationally designed peptides displaying sequences with high helical propensity. The folding/unfolding dynamics and energetics of α-helix conformations in naturally occurring peptides remains largely unexplored. Here we report the study of a protein fragment analogue of the C-peptide from bovine pancreatic ribonuclease-A, RN80, a 13-amino acid residue peptide that adopts a highly populated helical conformation in aqueous solution...
March 20, 2018: Journal of Physical Chemistry. B
Tong Lu, Feihong Meng, Ying Wei, Yang Li, Chunyu Wang, Fei Li
The formation of prefibrillar intermediates is a key stage not only for the fibrillation of amyloid peptides but also for their cytotoxicity. The heterogeneous and transient nature of most prefibrillar intermediates make them difficult to be separated, identified, and characterized. Rat islet amyloid polypeptide (rIAPP) has a weak propensity of fibrillation under most solution conditions and is found to be cytotoxic, which enables us to characterize prefibrillar species formed at various oligomeric states and explore the mechanism of membrane damage by these oligomers...
March 20, 2018: Physical Chemistry Chemical Physics: PCCP
Daniel Mattle, Bernd Kuhn, Johannes Aebi, Marc Bedoucha, Demet Kekilli, Nathalie Grozinger, Andre Alker, Markus G Rudolph, Georg Schmid, Gebhard F X Schertler, Michael Hennig, Jörg Standfuss, Roger J P Dawson
In the degenerative eye disease retinitis pigmentosa (RP), protein misfolding leads to fatal consequences for cell metabolism and rod and cone cell survival. To stop disease progression, a therapeutic approach focuses on stabilizing inherited protein mutants of the G protein-coupled receptor (GPCR) rhodopsin using pharmacological chaperones (PC) that improve receptor folding and trafficking. In this study, we discovered stabilizing nonretinal small molecules by virtual and thermofluor screening and determined the crystal structure of pharmacologically stabilized opsin at 2...
March 19, 2018: Proceedings of the National Academy of Sciences of the United States of America
Anna J Komor, Andrew J Jasniewski, Lawrence Que, John D Lipscomb
Covering: up to 2017The participation of non-heme dinuclear iron cluster-containing monooxygenases in natural product biosynthetic pathways has been recognized only recently. At present, two families have been discovered. The archetypal member of the first family, CmlA, catalyzes β-hydroxylation of l-p-aminophenylalanine (l-PAPA) covalently linked to the nonribosomal peptide synthetase (NRPS) CmlP, thereby effecting the first step in the biosynthesis of chloramphenicol by Streptomyces venezuelae. CmlA houses the diiron cluster in a metallo-β-lactamase protein fold instead of the 4-helix bundle fold of nearly every other diiron monooxygenase...
March 19, 2018: Natural Product Reports
Ge Yang, Kun Yu, Jan Kubicek, Jörg Labahn
The data presented here are related to the research article entitled "Expression, purification, and preliminary characterization of human presenilin-2" [1]. Human Presenilin-2 is the catalytic subunit of γ-secretase and a possible calcium leakage channel (Kimberly et al., 2000; Tu et al., 2006) [2], [3]. HisPS2 which was obtained by overexpression in E. coli strain C43 (DE3) was extracted by detergent solubilisation. The sample isolation efficiency by detergents and the protein identification by mass spectrometry and western blot are described...
April 2018: Data in Brief
Sukhendu Mandal, Semanti Ghosh, Debabrata Sinha, Soham Seal, Avisek Mahapa, Soumitra Polley, Deeya Saha, Keya Sau, Angshuman Bagchi, Subrata Sau
SarA, a winged-helix DNA binding protein, is a global virulence regulator in Staphylococcus aureus. The putative DNA binding region of SarA is located between amino acid residues Leu 53 and Gln 97. Previous studies have demonstrated that residues at positions 84, 88, 89, and 90 are critical for its function. To precisely understand the roles of the DNA binding residues, we have investigated nine mutants of a recombinant SarA (rSarA) along with the rSarA mutants carrying mutations at the above four positions...
March 12, 2018: International Journal of Biological Macromolecules
Yoshinori Hirano, Yu Amano, Shigenobu Yonemura, Toshio Hakoshima
Mechanotransduction by α-catenin facilitates the force-dependent development of adherens junctions (AJs) by recruiting vinculin to reinforce actin anchoring of AJs. The α-catenin mechanotransducing action is facilitated by its force-sensing device region that autoinhibits the vinculin-binding site 1 (VBS1). Here, we report the high-resolution structure of the force-sensing device region of α-catenin, which shows the autoinhibited form comprised of helix bundles E, F and G. The cryptic VBS1 is embedded into helix bundle E stabilized by direct interactions with the autoinhibitory region forming helix bundles F and G...
March 15, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Meng-Ting Li, Ning Kong, Ya-Qian Lan, Zhong-Min Su
We utilise the dual synthesis strategy in terms of bimetallic inorganic building blocks and sulfur containing organic ligand. A novel sulfur-containing bimetallic metal organic framework (Fe2 Co-TPDC) with two types of 4-fold meso-helical structures has been successfully synthesized. Benefitting from the uniform distribution of active sulfur sites and the structural stability of the mixed-metallic method, Fe2 Co-TPDC can efficiently prevent a shuttle behavior of sulfur and endow a commendable specific capacity...
March 15, 2018: Dalton Transactions: An International Journal of Inorganic Chemistry
Yan Yan, Yue Ding, Fenfei Leng, David Dunlap, Laura Finzi
Supercoiling can alter the form and base pairing of the double helix and directly impact protein binding. More indirectly, changes in protein binding and the stress of supercoiling also influence the thermodynamic stability of regulatory, protein-mediated loops and shift the equilibria of fundamental DNA/chromatin transactions. For example, supercoiling affects the hierarchical organization and function of chromatin in topologically associating domains (TADs) in both eukaryotes and bacteria. On the other hand, a protein-mediated loop in DNA can constrain supercoiling within a plectonemic structure...
March 10, 2018: Nucleic Acids Research
Brooke Anderson, Ramanarayanan Krishnamurthy
Pyrophosphate linkages are important in extant biology and are hypothesized to have played a role in prebiotic chemistry and in the origination of oligonucleotides. Inspired by the possible role of pyrophosphate as backbones of primordial oligomers, we synthesized DNA oligomers with varying amounts of pyrophosphate inserts (ppDNA) and investigated their base-pairing properties. As expected, with increasing amounts of pyrophosphate inserts in the backbone the thermal stability of ppDNA-DNA duplexes was compromised...
March 12, 2018: Chemistry: a European Journal
Hui Huang, Georg Kuenze, Jarrod A Smith, Keenan C Taylor, Amanda M Duran, Arina Hadziselimovic, Jens Meiler, Carlos G Vanoye, Alfred L George, Charles R Sanders
Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure...
March 2018: Science Advances
Manish Kesherwani, Devadasan Velmurugan
Undecaprenyl phosphate (C55-P) acts as carrier lipid in the synthesis of peptidoglycan, which is de novo synthesized from dephosphorylation of undecaprenyl pyrophosphate (C55-PP). The phosphatidylglycerol phosphate phosphatase B (PgpB) catalyzes the dephosphorylation of C55-PP and forms C55-P. As no structural study has been made regarding the binding of C55-PP to PgpB, in the current study, in silico molecular docking, followed by 150 ns molecular dynamics simulation of the putative binding complex in membrane/solvent environment has been performed to understand conformational dynamics...
March 12, 2018: Journal of Biomolecular Structure & Dynamics
Soung-Hun Roh, Nicholas J Stam, Corey F Hryc, Sergio Couoh-Cardel, Grigore Pintilie, Wah Chiu, Stephan Wilkens
The molecular mechanism of transmembrane proton translocation in rotary motor ATPases is not fully understood. Here, we report the 3.5-Å resolution cryoEM structure of the lipid nanodisc-reconstituted Vo proton channel of the yeast vacuolar H+ -ATPase, captured in a physiologically relevant, autoinhibited state. The resulting atomic model provides structural detail for the amino acids that constitute the proton pathway at the interface of the proteolipid ring and subunit a. Based on the structure and previous mutagenesis studies, we propose the chemical basis of transmembrane proton transport...
March 7, 2018: Molecular Cell
Sean P Cornillie, Benjamin J Bruno, Carol S Lim, Thomas E Cheatham
The oncogenic gene product Bcr-Abl is the principal cause of chronic myeloid leukemia (CML) and though several therapies exist to curb the aberrant kinase activity of Bcr-Abl through targeting of the Abl kinase domain, these therapies are rendered ineffective by frequent mutations in the corresponding gene. It has been demonstrated that a designed protein known as CCmut3 is able to produce a dominant negative inactivating effect on Bcr-Abl kinase by preferentially oligomerizing with the N-terminal coiled-coil oligomerization domain of Bcr-Abl (Bcr-CC) to effectively reduce the oncogenic potential of Bcr-Abl...
March 8, 2018: Journal of Physical Chemistry. B
Selena G Burgess, Manjeet Mukherjee, Sarah Sabir, Nimesh Joseph, Cristina Gutiérrez-Caballero, Mark W Richards, Nicolas Huguenin-Dezot, Jason W Chin, Eileen J Kennedy, Mark Pfuhl, Stephen J Royle, Fanni Gergely, Richard Bayliss
Aurora-A regulates the recruitment of TACC3 to the mitotic spindle through a phospho-dependent interaction with clathrin heavy chain (CHC). Here, we describe the structural basis of these interactions, mediated by three motifs in a disordered region of TACC3. A hydrophobic docking motif binds to a previously uncharacterized pocket on Aurora-A that is blocked in most kinases. Abrogation of the docking motif causes a delay in late mitosis, consistent with the cellular distribution of Aurora-A complexes. Phosphorylation of Ser558 engages a conformational switch in a second motif from a disordered state, needed to bind the kinase active site, into a helical conformation...
March 6, 2018: EMBO Journal
Maria Luisa Lopez-Redondo, Nicolas Coudray, Zhening Zhang, John Alexopoulos, David L Stokes
YiiP is a dimeric antiporter from the cation diffusion facilitator family that uses the proton motive force to transport Zn2+ across bacterial membranes. Previous work defined the atomic structure of an outward-facing conformation, the location of several Zn2+ binding sites, and hydrophobic residues that appear to control access to the transport sites from the cytoplasm. A low-resolution cryo-EM structure revealed changes within the membrane domain that were associated with the alternating access mechanism for transport...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Aviv Paz, Derek P Claxton, Jay Prakash Kumar, Kelli Kazmier, Paola Bisignano, Shruti Sharma, Shannon A Nolte, Terrin M Liwag, Vinod Nayak, Ernest M Wright, Michael Grabe, Hassane S Mchaourab, Jeff Abramson
Sodium-dependent transporters couple the flow of Na+ ions down their electrochemical potential gradient to the uphill transport of various ligands. Many of these transporters share a common core structure composed of a five-helix inverted repeat and deliver their cargo utilizing an alternating-access mechanism. A detailed characterization of inward-facing conformations of the Na+ -dependent sugar transporter from Vibrio parahaemolyticus (vSGLT) has previously been reported, but structural details on additional conformations and on how Na+ and ligand influence the equilibrium between other states remains unknown...
March 5, 2018: Proceedings of the National Academy of Sciences of the United States of America
Mehmet Sen, Adem C Koksal, Koichi Yuki, Jianchuan Wang, Timothy A Springer
In αI integrins including leukocyte function-associated antigen-1 (LFA-1), ligand-binding function is delegated to the αI domain, requiring extra steps in the relay of signals that activate ligand binding and coordinate it with cytoplasmic signals. Crystal structures reveal great variation in orientation between the αI domain and the remainder of the integrin head. Here, we investigated the mechanisms involved in signal relay to the αI domain, including whether binding of the ligand intercellular adhesion molecule-1 (ICAM-1) to the αI domain is linked to headpiece opening and engenders a preferred αI domain orientation...
March 5, 2018: Journal of Biological Chemistry
Oluwatoyin A Asojo, Rabih Darwiche, Selam Gebremedhin, Geert Smant, Jose L Lozano-Torres, Claire Drurey, Jeroen Pollet, Rick M Maizels, Roger Schneiter, Ruud H P Wilbers
Heligmosomoides polygyrus bakeri is a model parasitic hookworm used to study animal and human helminth diseases. During infection, the parasite releases excretory/secretory (ES) products that modulate the immune system of the host. The most abundant protein family in ES products comprises the venom allergen-like proteins (VALs), which are members of the SCP/TAPS (Sperm-coating protein / Tpx / antigen 5 / pathogenesis related-1 / Sc7) superfamily. There are >30 secreted Heligmosomoides polygyrus VAL proteins (HpVALs) and these proteins are characterized by having either one or two 15 kDa CAP (cysteine-rich secretory protein (CRISP) / antigen 5 / pathogenesis related-1) domains...
March 2, 2018: International Journal for Parasitology
T K Bijoy, P Murugan, Vijay Kumar
We study the structural stability and electronic properties of new classes of DNA-like inorganic double helices of the type A2 B2 XY (A = Si-Pb, B = Cl-I, and XY = PN and SiS) by employing first principles density functional theory (DFT) calculations including van der Waals interactions. In these quaternary double helices PN or SiS forms the inner helix while the AB helix wraps around the inner helix and the two are interconnected. We find that the bromides and iodides of Ge, Sn, and Pb as well as Pb2 Cl2 PN form structurally stable double helices while Ge2 I2 SiS as well as bromides and iodides of Sn and Pb have stable double helices...
March 5, 2018: Physical Chemistry Chemical Physics: PCCP
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