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Protein Science: a Publication of the Protein Society

Sarah G Nowakowski, Michael Regnier, Valerie Daggett
Myosin activation is a viable approach to treat systolic heart failure. We previously demonstrated that striated muscle myosin is a promiscuous ATPase that can use most nucleoside triphosphates as energy substrates for contraction. When 2-deoxy ATP (dATP) is used, it acts as a myosin activator, enhancing cross-bridge binding and cycling. In vivo, we have demonstrated that elevated dATP levels increase basal cardiac function and rescues function of infarcted rodent and pig hearts. Here we investigate the molecular mechanism underlying this physiological effect...
January 18, 2017: Protein Science: a Publication of the Protein Society
Sotaro Fujii, Hiroya Oki, Kazuki Kawahara, Daisuke Yamane, Masaru Yamanaka, Takahiro Maruno, Yuji Kobayashi, Misa Masanari, Satoshi Wakai, Hirofumi Nishihara, Tadayasu Ohkubo, Yoshihiro Sambongi
Thermophilic Hydrogenophilus thermoluteolus cytochrome c' (PHCP) exhibits higher thermal stability than a mesophilic counterpart, Allochromatium vinosum cytochrome c' (AVCP), which has a homo-dimeric structure and ligand-binding ability. To understand the thermal stability mechanism and ligand-binding ability of the thermally stable PHCP protein, the crystal structure of PHCP was first determined. It formed a homo-dimeric structure, the main chain root mean square deviation (rmsd) value between PHCP and AVCP being 0...
January 18, 2017: Protein Science: a Publication of the Protein Society
Naveed A Nadvi, Noeris K Salam, Joohong Park, Fady N Akladios, Vimal Kapoor, Charles A Collyer, Mark D Gorrell, And W Bret Church
In this study we report two high-resolution structures of the pyridoxal 5' phosphate (PLP)-dependent enzyme kynurenine aminotransferase-I (KAT-I). One is the native structure with the cofactor in the PLP form bound to Lys247 with the highest resolution yet available for KAT-I at 1.28 Å resolution, and the other with the general PLP-dependent aminotransferase inhibitor, aminooxyacetate (AOAA) covalently bound to the cofactor at 1.54 Å. Only small conformational differences are observed in the vicinity of the aldimine (oxime) linkage with which the PLP forms the Schiff base with Lys247 in the 1...
January 18, 2017: Protein Science: a Publication of the Protein Society
Juliana Sakamoto Yoneda, Andew J Miles, Ana Paula Ulian de Araujo, B A Wallace
Globular proteins composed of different secondary structures and fold types were examined by synchrotron radiation circular dichroism spectroscopy to determine the effects of dehydration on their secondary structures. They exhibited only minor changes upon removal of bulk water during film formation, contrary to previously reported studies of proteins dehydrated by lyophilisation (where substantial loss of helical structure and gain in sheet structure was detected). This near lack of conformational change observed for globular proteins contrasts with intrinsically disordered proteins (IDPs) dried in the same manner: the IDPs, which have almost completely unordered structures in solution, exhibited increased amounts of regular (mostly helical) secondary structures when dehydrated, suggesting formation of new intra-protein hydrogen bonds replacing solvent-protein hydrogen bonds, in a process which may mimic interactions that occur when IDPs bind to partner molecules...
January 18, 2017: Protein Science: a Publication of the Protein Society
Yongli Zhang
Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are universal molecular engines that drive membrane fusion. Particularly, synaptic SNAREs mediate fast calcium-triggered fusion of neurotransmitter-containing vesicles with plasma membranes for synaptic transmission, the basis of all thought and action. During membrane fusion, complementary SNAREs located on two apposed membranes (often called t- and v-SNAREs) join together to assemble into a parallel four-helix bundle, releasing the energy to overcome the energy barrier for fusion...
January 18, 2017: Protein Science: a Publication of the Protein Society
Zsolt Mártonfalvi, Pasquale Bianco, Katalin Naftz, György G Ferenczy, Miklós Kellermayer
Titin is a giant protein that provides elasticity to muscle. As the sarcomere is stretched, titin extends hierarchically according to the mechanics of its segments. Whether titin's globular domains unfold during this process and how such unfolded domains might contribute to muscle contractility are strongly debated. To explore the force-dependent folding mechanisms, here we manipulated skeletal-muscle titin molecules with high-resolution optical tweezers. In force-clamp mode, after quenching the force (<10 pN), extension fluctuated without resolvable discrete events...
January 18, 2017: Protein Science: a Publication of the Protein Society
Meghan C Ferrall-Fairbanks, Zachary T Barry, Maurizio Affer, Marc A Shuler, Ellen W Moomaw, Manu O Platt
Multiple proteases in a system hydrolyze target substrates, but recent evidence indicates that some proteases will degrade other proteases as well. Cathepsin S hydrolysis of cathepsin K is one such example. These interactions may be uni- or bi-directional and change the expected kinetics. To explore potential protease-on-protease interactions in silico, a program was developed for users to input two proteases: 1) the protease-ase that hydrolyzes 2) the substrate, protease. This program identifies putative sites on the substrate protease highly susceptible to cleavage by the protease-ase, using a sliding window approach that scores amino acid sequences by their preference in the protease-ase active site, culled from MEROPS database...
January 12, 2017: Protein Science: a Publication of the Protein Society
Piero R Bianco, Yuri L Lyubchenko
In E. coli, the regression of stalled DNA replication forks is catalyzed by the DNA helicase RecG. One means of gaining access to the fork is by binding to the single strand binding protein or SSB. This interaction occurs via the wedge domain of RecG and the intrinsically disordered linker (IDL) of SSB, in a manner similar to that of SH3 domains binding to PXXP motif-containing ligands in eukaryotic cells. During loading, SSB remodels the wedge domain so that the helicase domains bind to the parental, duplex DNA, permitting the helicase to translocate using thermal energy...
January 12, 2017: Protein Science: a Publication of the Protein Society
Hui Yin Tan, Luke A Wilczek, Sasheen Pottinger, Maria Manosas, Cong Yu, Trong Nguyenduc, Piero R Bianco
The Escherichia coli single stranded DNA binding protein (SSB) is crucial for DNA replication, recombination and repair. Within each process, it has two seemingly disparate roles: it stabilizes single-stranded DNA (ssDNA) intermediates generated during DNA processing and, forms complexes with a group of proteins known as the SSB-interactome. Key to both roles is the C-terminal, one-third of the protein, in particular the intrinsically disordered linker (IDL). Previously, we have shown using a series of linker deletion mutants that the IDL links both ssDNA and target protein binding by mediating interactions with the oligosaccharide/oligonucleotide binding fold in the target...
January 12, 2017: Protein Science: a Publication of the Protein Society
Stacy T Knutson, Brian M Westwood, Janelle B Leuthaeuser, Brandon Turner, Don Nguyendac, Gabrielle Shea, Kiran Kumar, Julia Hayden, Angela Harper, Shoshana D Brown, John H Morris, Thomas E Ferrin, Patricia C Babbitt, Jacquelyn S Fetrow
Protein function identification remains a significant problem. Solving this problem at the molecular functional level would allow mechanistic determinant identification -amino acids that distinguish details between functional families within a superfamily. Active site profiling was developed to identify mechanistic determinants. DASP and DASP2 were developed as tools to search sequence databases using active site profiling. Here, TuLIP (Two-Level Iterative clustering Process) is introduced as an iterative, divisive clustering process that utilizes active site profiling to separate structurally characterized superfamily members into functionally relevant clusters...
January 5, 2017: Protein Science: a Publication of the Protein Society
Thomas C Custer, Nils G Walter
RNA plays a fundamental, ubiquitous role as either substrate or functional component of many large cellular complexes - 'molecular machines' - used to maintain and control the readout of most genetic information, a functional landscape that we are only beginning to understand. The cellular mechanisms for the spatiotemporal organization of the plethora of RNAs involved in gene expression are particularly poorly understood. Intracellular single-molecule fluorescence microscopy provides a powerful emerging tool for probing the pertinent mechanistic parameters that govern cellular RNA functions, including those of protein coding messenger RNAs (mRNAs)...
December 28, 2016: Protein Science: a Publication of the Protein Society
Garrett T Dow, Michel Gilbert, James B Thoden, Hazel M Holden
Campylobacter jejuni is a Gram-negative bacterium that represents a leading cause of human gastroenteritis worldwide. Of particular concern is the link between C. jejuni infections and the subsequent development of Guillain-Barré syndrome, an acquired autoimmune disorder leading to paralysis. All Gram-negative bacteria contain complex glycoconjugates anchored to their outer membranes, but in most strains of C. jejuni, this lipoglycan lacks the O-antigen repeating units. Recent mass spectrometry analyses indicate that the C...
December 28, 2016: Protein Science: a Publication of the Protein Society
Sarah E Herlihy, Yu Tang, Jonathan E Phillips, Richard H Gomer
Autocrine proliferation repressor protein A (AprA) is a protein secreted by Dictyostelium discoideum cells. Although there is very little sequence similarity between AprA and any human protein, AprA has a predicted structural similarity to the human protein Dipeptidyl Peptidase IV (DPPIV). AprA is a chemorepellent for Dictyostelium cells, and DPPIV is a chemorepellent for neutrophils. This led us to investigate if AprA and DPPIV have additional functional similarities. We find that like AprA, DPPIV is a chemorepellent for, and inhibits the proliferation of, D...
December 28, 2016: Protein Science: a Publication of the Protein Society
Ying-Chih Chi, Jeremy T Rahkola, Agnieszka A Kendrick, Michael J Holliday, Natasia Paukovich, Thomas S Roberts, Edward N Janoff, Elan Z Eisenmesser
IgA1 proteases (IgA1P) from diverse pathogenic bacteria specifically cleave human immunoglobulin A1 (IgA1) at the hinge region, thereby thwarting protective host immune responses. Streptococcus pneumoniae (S. pneumoniae) IgA1P shares no sequence conservation with serine or cysteine types of IgA1Ps or other known proteins, other than a conserved HExxH Zn-binding motif (1604-1608) found in metalloproteases. We have developed a novel expression system to produce the mature S. pneumoniae IgA1P and we have discovered that this form is both attached to the bacterial cell surface and release in its full form...
December 28, 2016: Protein Science: a Publication of the Protein Society
Alizée Vergès, Emmanuelle Cambon, Sophie Barbe, Claire Moulis, Magali Remaud-Siméon, Isabelle André
A computer-aided engineering approach recently enabled to deeply reshape the active site of N. polysaccharea amylosucrase for recognition of non-natural acceptor substrates. Libraries of variants were constructed and screened on sucrose allowing the identification of 17 mutants able to synthesize molecules from sole sucrose, which are not synthesized by the parental wild-type enzyme. Three of the isolated mutants as well as the new products synthesized were characterized in details. Mutants contain between 7 and 11 mutations in the active site and the new molecules were identified as being a sucrose derivative, named erlose (α-D-glucopyranosyl-(1→4)-α-D-glucopyranosyl-(1→2)-β-D-Fructose), and a new malto-oligosaccharide named panose (α-D-glucopyranosyl-(1→6)-α-D-glucopyranosyl-(1→4)-α-D-Glucose)...
December 26, 2016: Protein Science: a Publication of the Protein Society
Kaare Teilum, Micha Ben Achim Kunze, Simon Erlendsson, Birthe B Kragelund
Protein molecules are highly diverse communication platforms and their interaction repertoire stretches from atoms over small molecules such as sugars and lipids to macromolecules. An important route to understanding molecular communication is to quantitatively describe their interactions. These types of analyses determine the amounts and proportions of individual constituents that participate in a reaction as well as their rates of reactions and their thermodynamics. Although many different methods are available, there is currently no single method able to quantitatively capture and describe all types of protein reactions, which can span orders of magnitudes in affinities, reaction rates and lifetimes of states...
December 26, 2016: Protein Science: a Publication of the Protein Society
Haydeé Mesa-Galloso, Karelia H Delgado-Magnero, Sheila Cabezas, Aracelys López-Castilla, Jorge E Hernández-González, Lohans Pedrera, Carlos Alvarez, D Peter Tieleman, Ana J García-Saez, Maria E Lanio, Uris Ros, Pedro A Valiente
Crystallographic data of the dimeric and octameric forms of fragaceatoxin C (FraC) suggested the key role of a small hydrophobic protein-protein interaction surface for actinoporins oligomerization and pore formation in membranes. However, site-directed mutagenesis studies supporting this hypothesis for others actinoporins are still lacking. Here, we demonstrate that disrupting the key hydrophobic interaction between V60 and F163 (FraC numbering scheme) in the oligomerization interface of FraC, equinatoxin II (EqtII) and sticholysin II (StII) impairs the pore formation activity of these proteins...
December 21, 2016: Protein Science: a Publication of the Protein Society
John M Hickey, Neha Sahni, Rajoshi Chaudhuri, Ajit D'Souza, Andrew Metters, Sangeeta B Joshi, C Russell Middaugh, David B Volkin
Continuous glucose monitoring (CGM) devices offer diabetes patients a convenient approach to assist in controlling blood glucose levels. A prototype CGM has been developed that uses the emission profile of a polarity-sensitive fluorophore (acrylodan) conjugated to a glucose/galactose-binding protein (SM4-AC) to measure the concentration of glucose in vivo. During development, a decrease in the devices signal intensity was observed in vivo over time, which was postulated to be result of oxidative degradation of SM4-AC...
December 20, 2016: Protein Science: a Publication of the Protein Society
Amrita Kundu, Sangeeta Kundu, Krishnananda Chattopadhyay
MPT63, a major secreted protein from Mycobacterium tuberculosis, has been shown to have immunogenic properties and has been implicated in virulence. MPT63 is a β-sandwich protein containing 11 β strands and a very short stretch of 310 helix. The detailed experimental and computational study reported here investigates the equilibrium unfolding transition of MPT63. It is shown that in spite of being a complete β-sheet protein, MPT63 has a strong propensity towards helix structures in its early intermediates...
December 20, 2016: Protein Science: a Publication of the Protein Society
Kirill D Nadezhdin, Daria D Romanovskaia, Maria Y Sachkova, Peter B Oparin, Sergey I Kovalchuk, Eugene V Grishin, Alexander S Arseniev, Alexander A Vassilevski
We have recently demonstrated that a common phenomenon in evolution of spider venom composition is the emergence of so-called modular toxins consisting of two domains, each corresponding to a "usual" single-domain toxin. In this paper, we describe the structure of two domains that build up a modular toxin named spiderine or OtTx1a from the venom of Oxyopes takobius. Both domains were investigated by solution NMR in water and detergent micelles used to mimic membrane environment. The N-terminal spiderine domain OtTx1a-AMP (41 amino acid residues) contains no cysteines...
December 20, 2016: Protein Science: a Publication of the Protein Society
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