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membrane protein folding

Marian L Miller, Aleksey Porollo, Susan Wert
Alveolar type II cells from seven mammalian species were examined for a protein in the rough endoplasmic reticulum (RER), which showed a multi-layered, repeating motif. Each motif, 100nm in width, comprised two parallel outer dense layers, a less dense central layer, and often 1-3 faint layers on either side of the latter. Outer layers showed periodicities at 3-4 densities/100nm of width, while layers on either side of the central layer showed 5-7 densities/100nm of width. RER membranes were ribosome-free when parallel to these layers, but showed 4 ribosomes per motif at the growing ends: one ribosome at each outer dense layer, and one on either side of the less dense central layer...
March 15, 2018: Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology
Charles K Davis, Sreekala S Nampoothiri, G K Rajanikant
The constant failure of single-target drug therapies for ischemic stroke necessitates the development of novel pleiotropic pharmacological treatment approaches, to effectively combat the aftermath of this devastating disorder. The major objective of our study involves a multi-target drug repurposing strategy to stabilize hypoxia-inducible factor-1 α (HIF-1α) via a structure-based screening approach to simultaneously inhibit its regulatory proteins, PHD2, FIH, and pVHL. Out of 1424 Food and Drug Administration (FDA)-approved drugs that were screened, folic acid (FA) emerged as the top hit and its binding potential to PHD2, FIH, and pVHL was further verified by re-docking, molecular dynamics (MD) simulation and by Drug Affinity Responsive Target Stability (DARTS) assay...
March 14, 2018: Molecular Neurobiology
Geoffrey Masuyer, Sicai Zhang, Sulyman Barkho, Yi Shen, Linda Henriksson, Sara Košenina, Min Dong, Pål Stenmark
Botulinum neurotoxins (BoNTs) are among the most potent toxins known and are also used to treat an increasing number of medical disorders. There are seven well-established serotypes (BoNT/A-G), which all act as zinc-dependent endopeptidases targeting specific members of the SNARE proteins required for synaptic vesicle exocytosis in neurons. A new toxin serotype, BoNT/X, was recently identified. It cleaves not only the canonical targets, vesicle associated membrane proteins (VAMP) 1/2/3 at a unique site, but also has the unique ability to cleave VAMP4/5 and Ykt6...
March 14, 2018: Scientific Reports
Asghar M Razavi, George Khelashvili, Harel Weinstein
BACKGROUND: Much of the structure-based mechanistic understandings of the function of SLC6A neurotransmitter transporters emerged from the study of their bacterial LeuT-fold homologs. It has become evident, however, that structural differences such as the long N- and C-termini of the eukaryotic neurotransmitter transporters are involved in an expanded set of functional properties to the eukaryotic transporters. These functional properties are not shared by the bacterial homologs, which lack the structural elements that appeared later in evolution...
March 14, 2018: BMC Biology
Roshan Kumar, Raniki Kumari, Sanjay Kumar, Deepak Kumar Jangir, Tushar Kanti Maiti
α-Synuclein, a major constituent of proteinaceous inclusions named Lewy body, has been shown to be released and taken up by cells, which may facilitate its progressive pathological spreading and neuronal cell death in Parkinson's disease. However, the pathophysiological effect and signalling cascade initiated by extracellular α-synuclein in cellular milieu are not well understood. Herein we have investigated the perturbations induced by low molecular weight α-synuclein and different types of α-synuclein oligomers in the neuroblastoma SH-SY5Y cells...
March 14, 2018: Biomacromolecules
Mingming Pu, Lili Sheng, Sooyeon Song, Ting Gong, Thomas K Wood
Pseudomonas aeruginosa causes many biofilm infections, and the rugose small-colony variants (RSCVs) of this bacterium are important for infection. We found here that inactivation of PA2444, which we determined to be a serine hydroxymethyltransferase (SHMT), leads to the RSCV phenotype of P. aeruginosa PA14. In addition, loss of PA2444 increases biofilm formation by two orders of magnitude, increases exopolysaccharide by 45-fold, and abolishes swarming. The RSCV phenotype is related to higher cyclic diguanylate concentrations due to increased activity of the Wsp chemosensory system, including diguanylate cyclase WspR...
2018: Frontiers in Microbiology
Julia Koehler Leman, Richard Bonneau, Martin B Ulmschneider
Modeling membrane protein (MP) folding, insertion, association and their interactions with other proteins, lipids, and drugs requires accurate transfer free energies (TFEs). Various TFE scales have been derived to quantify the energy required or released to insert an amino acid or protein into the membrane. Experimental measurement of TFEs is challenging, and only few scales were extended to depth-dependent energetic profiles. Statistical approaches can be used to derive such potentials; however, this requires a sufficient number of MP structures...
March 13, 2018: Scientific Reports
S Hollingshead, I Jongerius, R M Exley, S Johnson, S M Lea, C M Tang
There is an urgent need to develop vaccines against pathogenic bacteria. However, this is often hindered by antigenic diversity and difficulties encountered manufacturing membrane proteins. Here we show how to use structure-based design to develop chimeric antigens (ChAs) for subunit vaccines. ChAs are generated against serogroup B Neisseria meningitidis (MenB), the predominant cause of meningococcal disease in wealthy countries. MenB ChAs exploit factor H binding protein (fHbp) as a molecular scaffold to display the immunogenic VR2 epitope from the integral membrane protein PorA...
March 13, 2018: Nature Communications
Bo Hou, Eyleen S Heidrich, Denise Mehner-Breitfeld, Thomas Brüser
The twin-arginine translocation (Tat) system that comprises the TatA, TatB, and TatC components transports folded proteins across energized membranes of prokaryotes and plant plastids. It is not known, however, how the transport of this protein cargo is achieved. Favored models suggest that the TatA component supports transport by weakening the membrane upon full translocon assembly. Using Escherichia coli as model organism, we now demonstrate in vivo that the N-terminus of TatA can indeed destabilize the membrane, resulting in a lowered membrane energization in growing cells...
March 13, 2018: Journal of Biological Chemistry
A Mostek, M Slowinska, S Judycka, H Karol, A Ciereszko, M A Dietrich
During semen cryopreservation, spermatozoa are exposed to physical and chemical stressors that result in their functional and structural damage. Growing evidence suggests that most cryoinjuries result from oxidative stress accompanying sperm cryopreservation. Elevated amounts of reactive oxygen species (ROS) generated during cryopreservation can react with sperm macromolecules, including proteins. The goal of this study was to investigate the oxidative modifications (measured as carbonylation level changes) of carp spermatozoa proteins triggered by the cryopreservation process...
March 9, 2018: Journal of Animal Science
Eny Kusrini, Fatimah Hashim, Cindy Gunawan, Riti Mann, Wan Nor Nadhirah Wan Noor Azmi, Nakisah Mat Amin
This work investigated the anti-amoebic activity of two samarium (Sm) complexes, the acyclic complex [bis(picrato)(pentaethylene glycol)samarium(III)] picrate-referred to as [Sm(Pic)2 (EO5)](Pic)-and the cyclic complex [bis(picrato)(18-crown-6)samarium(III)] picrate-referred to as [Sm(Pic)2 (18C6)](Pic). Both Sm complexes caused morphological transformation of the protozoa Acanthamoeba from its native trophozoite form carrying a spine-like structure called acanthopodia, to round-shaped cells with loss of the acanthopodia structure, a trademark response to environmental stress...
March 12, 2018: Parasitology Research
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
Martyna Szpakowska, Max Meyrath, Nathan Reynders, Manuel Counson, Julien Hanson, Jan Steyaert, Andy Chevigné
The atypical chemokine receptor ACKR3/CXCR7 plays crucial roles in numerous physiological processes but also in viral infection and cancer. ACKR3 shows strong propensity for activation and, unlike classical chemokine receptors, can respond to chemokines from both the CXC and CC families as well as to the endogenous peptides BAM22 and adrenomedullin. Moreover, despite belonging to the G protein coupled receptor family, its function appears to be mainly dependent on β-arrestin. ACKR3 has also been shown to continuously cycle between the plasma membrane and the endosomal compartments, suggesting a possible role as a scavenging receptor...
March 9, 2018: Biochemical Pharmacology
Yiqing Yang, Ruiqiong Guo, Kristen Gaffney, Miyeon Kim, Shaima Muhammednazaar, Wei Tian, Boshen Wang, Jie Liang, Heedeok Hong
ATP-dependent protein degradation mediated by AAA+ proteases is one of the major cellular pathways for protein quality control and regulation of functional networks. While a majority of studies of protein degradation have focused on water-soluble proteins, it is not well understood how membrane proteins with abnormal conformation are selectively degraded. The knowledge gap stems from the lack of an in vitro system in which detailed molecular mechanisms can be studied as well as difficulties in studying membrane protein folding in lipid bilayers...
March 12, 2018: Journal of the American Chemical Society
Mario Mardirossian, Natacha Pérébaskine, Monica Benincasa, Stefano Gambato, Sven Hofmann, Paul Huter, Claudia Müller, Kai Hilpert, C Axel Innis, Alessandro Tossi, Daniel N Wilson
Proline-rich antimicrobial peptides (PrAMPs) internalize into susceptible bacteria using specific transporters and interfere with protein synthesis and folding. To date, mammalian PrAMPs have so far been identified only in artiodactyls. Since cetaceans are co-phyletic with artiodactyls, we mined the genome of the bottlenose dolphin Tursiops truncatus, leading to the identification of two PrAMPs, Tur1A and Tur1B. Tur1A, which is orthologous to the bovine PrAMP Bac7, is internalized into Escherichia coli, without damaging the membranes, using the inner membrane transporters SbmA and YjiL/MdM...
February 22, 2018: Cell Chemical Biology
Yan Xia, Axel W Fischer, Pedro Teixeira, Brian Weiner, Jens Meiler
While great progress has been made, only 10% of the nearly 1,000 integral, α-helical, multi-span membrane protein families are represented by at least one experimentally determined structure in the PDB. Previously, we developed the algorithm BCL::MP-Fold, which samples the large conformational space of membrane proteins de novo by assembling predicted secondary structure elements guided by knowledge-based potentials. Here, we present a case study of rhodopsin fold determination by integrating sparse and/or low-resolution restraints from multiple experimental techniques including electron microscopy, electron paramagnetic resonance spectroscopy, and nuclear magnetic resonance spectroscopy...
February 23, 2018: Structure
Anja Schiffmann, Gerald Gimpl
The oxytocin receptor, a class A G protein coupled receptor (GPCR), is essentially involved in the physiology of reproduction. Two parameters are crucially important to support high-affinity agonist binding of the receptor: Mg2+ and cholesterol, both acting as positive modulators. Using displacement assays with a high-affinity fluorescent antagonist (OTAN-A647), we now show that sodium functions as a negative allosteric modulator of the oxytocin receptor. In membranes from HEK293 cells stably expressing the oxytocin receptor, oxytocin binding occurred with about 15-fold lower affinity when sodium chloride was increased from 0 to 300 mM, whereas antagonist binding remained largely unchanged...
March 7, 2018: Biochimica et Biophysica Acta
Gunnar von Heijne
My scientific career has taken me from chemistry, via theoretical physics and bioinformatics, to molecular biology and even structural biology. Along the way, serendipity led me to work on problems such as the identification of signal peptides that direct protein trafficking, membrane protein biogenesis, and cotranslational protein folding. I've had some great collaborations that came about because of a stray conversation or from following up on an interesting paper. And I've had the good fortune to be asked to sit on the Nobel Committee for Chemistry, where I am constantly reminded of the amazing pace and often intricate history of scientific discovery...
March 9, 2018: Journal of Biological Chemistry
Qingwen Wan, Najeah Okashah, Asuka Inoue, Rony Nehmé, Byron Carpenter, Christopher G Tate, Nevin A Lambert
G protein-coupled receptors (GPCRs) are key signaling proteins that regulate nearly every aspect of cell function. Studies of GPCRs have benefitted greatly from the development of molecular tools to monitor receptor activation and downstream signaling. Here we show that mini G proteins are robust probes that can be used in a variety of assay formats to report GPCR activity in living cells. Mini G (mG) proteins are engineered GTPase domains of Gα subunits that were developed for structural studies of active state GPCRs...
March 9, 2018: Journal of Biological Chemistry
Debra T Hansen, Felicia M Craciunescu, Petra Fromme, Stephen A Johnston, Kathryn F Sykes
Membrane proteins are the molecular interface of the cell and its environs; however, studies of membrane proteins are highly technically challenging, mainly due to instability of the isolated protein. Towards the production of antibodies that recognize properly folded and stabilized forms of membrane protein antigen, we describe a DNA-based immunization method for mice that expresses the antigen in the membranes of dendritic cells, thus allowing direct presentation to the immune system. This genetic immunization approach employs a highly efficient method of biolistic delivery based on DNA-gold micronanoplexes, which are complexes of micron-sized gold particles that allow dermal penetration and nanometer-sized gold particles that provide a higher surface area for DNA binding than micron gold alone...
February 21, 2018: Current Protocols in Protein Science
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