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Protein Science: a Publication of the Protein Society

Alexander Rittner, Karthik S Paithankar, David Drexler, Aaron Himmler, Martin Grininger
Modularity is a fundamental property of megasynthases such as polyketide synthases (PKSs). In this study, we exploit the close resemblance between PKSs and animal FAS to re-engineer animal FAS to probe the modularity of the FAS/PKS family. Guided by sequence and structural information, we truncate and dissect animal FAS into its components, and reassemble them to generate new PKS-like modules as well as bimodular constructs. The novel re-engineered modules resemble all four common types of PKSs and demonstrate that this approach can be a powerful tool to deliver products with higher catalytic efficiency...
November 5, 2018: Protein Science: a Publication of the Protein Society
Sneha Roy, Rajiv Bhat
Oligomerization of γ-Synuclein is known to have implications for both neurodegeneration and cancer. Although it is known to co-exist with the fibrillar deposits of α-Synuclein (Lewy bodies), a hallmark in Parkinson's disease (PD), the effect of potential therapeutic modulators on the fibrillation pathway of γ-Syn remains unexplored. By a combined use of various biophysical tools and cytotoxicity assays we demonstrate that the flavonoid epigallocatechin-3-gallate (EGCG) significantly suppresses γ-Syn fibrillation by affecting its nucleation and binds with the unstructured, nucleus forming oligomers of γ-Syn to modulate the pathway to form α-helical containing higher-order oligomers (~158 kDa and ~ 670 kDa) that are SDS-resistant and conformationally restrained in nature...
November 5, 2018: Protein Science: a Publication of the Protein Society
Arthur J Arcinas, Stephanie J Maiocco, Sean J Elliott, Alexey Silakov, Squire J Booker
MiaB is a member of the methylthiotransferase subclass of the radical S-adenosylmethionine (SAM) superfamily of enzymes, catalyzing the methylthiolation of C2 of adenosines bearing an N6 -isopentenyl (i6 A) group found at position 37 in several tRNAs to afford 2-methylthio-N6 -(isopentenyl)adenosine (ms2 i6 A). MiaB uses a reduced [4Fe-4S]+ cluster to catalyze a reductive cleavage of SAM to generate a 5'-deoxyadenosyl 5'-radical (5'-dA•)-a required intermediate in its reaction-as well as an additional [4Fe-4S]2+ auxiliary cluster...
November 5, 2018: Protein Science: a Publication of the Protein Society
Gert-Jan Bekker, Benson Ma, Narutoshi Kamiya
Single domain antibodies (sdAbs) function like regular antibodies, however consist of only one domain. Because of their low molecular weight, sdAbs have advantages with respect to production and delivery to their targets and for applications such as antibody drugs and biosensors. Thus, sdAbs with high thermal stability are required. In this work, we chose seven sdAbs, which have a wide range of melting temperature (Tm ) values and known structures. We applied molecular dynamics (MD) simulations to estimate their relative stability and compared them with the experimental data...
November 5, 2018: Protein Science: a Publication of the Protein Society
Naomi L Haworth, Michael J Wouters, Morgan O Hunter, Lixia Ma, Merridee A Wouters
Some disulfide bonds perform important structural roles in proteins, but another group have functional roles via redox reactions. Forbidden disulfides are stressed disulfides found in recognisable protein contexts, which currently constitute more than 10% of all disulfides in the PDB. They likely have functional redox roles and constitute a major subset of all redox-active disulfides. The torsional strain of forbidden disulfides is typically higher than for structural disulfides, but not so high as to render them immediately susceptible to reduction under physionormal conditions...
November 1, 2018: Protein Science: a Publication of the Protein Society
V Piiadov, E Ares de Araújo, M Oliveira Neto, A F Craievich, I Polikarpov
Knowledge of molecular weight, oligomeric states and quaternary arrangements of proteins in solution is fundamental for understanding their molecular functions and activities. We describe here a program SAXSMoW 2.0 for robust and quick determination of molecular weight and oligomeric state of proteins in dilute solution, starting from a single experimental small-angle scattering intensity curve, I(q), measured on a relative scale. The first version of this calculator has been widely used during the last decade and applied to analyze experimental SAXS data of many proteins and protein complexes...
October 29, 2018: Protein Science: a Publication of the Protein Society
Ming-Daw Tsai
No abstract text is available yet for this article.
October 28, 2018: Protein Science: a Publication of the Protein Society
So Eun Kim, Kwang Yeon Hwang, Ki Hyun Nam
Fluorescent proteins (FPs) possess a wide variety of spectral properties that make them of widespread interest as optical markers. These proteins can be applied as pH indicators or metal biosensors. The discovery and characterization of new fluorescent proteins is expected to further extend their application. Here, we report the spectral and structural analysis of a red fluorescent protein from Acropora digitifera (designated AdRed). This protein shows a tetrameric state and is red emitting, with excitation and emission maxima at 567 and 612 nm, respectively...
October 28, 2018: Protein Science: a Publication of the Protein Society
Jimin Wang, Zachary B Smithline
Extensive evidence exists that DNA polymerases use two metal ions to catalyze the phosphoryl transfer reaction. Recently competing evidence emerged, arguing that a third metal ion, known as MnC, may be involved in catalysis. The binding of MnC was observed in crystal structures of the replication complexes of human polymerase (pol) η, pol β, and pol μ. Its occupancy (qMnC ) in the pol η replication complexes exhibited a strong correlation with the fractional concentration or the occupancy of the formed product pyrophosphate (qPPi ), i...
October 28, 2018: Protein Science: a Publication of the Protein Society
Gabriel Javitt, Iris Grossman-Haham, Assaf Alon, Efrat Resnick, Yael Mutsafi, Tal Ilani, Deborah Fass
The thioredoxin superfamily has expanded and diverged extensively throughout evolution such that distant members no longer show appreciable sequence homology. Nevertheless, redox-active thioredoxin-fold proteins functioning in diverse physiological contexts often share canonical amino acids near the active-site (di-)cysteine motif. Quiescin sulfhydryl oxidase 1 (QSOX1), a catalyst of disulfide bond formation secreted by fibroblasts, is a multi-domain thioredoxin superfamily enzyme with certain similarities to the protein disulfide isomerase (PDI) enzymes...
October 27, 2018: Protein Science: a Publication of the Protein Society
Daniel Saez, Rosine Dushime, Hanzhi Wu, Lourdes Beatriz Ramos Cordova, Kirtikar Shukla, Heather Brown-Harding, Cristina M Furdui, Allen W Tsang
Sulforaphane (SFN), a phytochemical found in broccoli and other cruciferous vegetables, is a potent antioxidant and anti-inflammatory agent with reported effects in cancer chemoprevention and suppression of infection with intracellular pathogens. Here we report on the impact of SFN on infection with Chlamydia trachomatis (Ct), a common sexually transmitted pathogen responsible for 131 million new cases annually worldwide. Astoundingly, we find that SFN as well as broccoli sprout extract (BSE) promote Ct infection of human host cells...
October 27, 2018: Protein Science: a Publication of the Protein Society
Claudia S Kielkopf, Madhubrata Ghosh, Ganesh S Anand, Simon H J Brown
Apolipoprotein-D is a glycosylated tetrameric lipocalin that binds and transports small hydrophobic molecules such as progesterone and arachidonic acid. Like other lipocalins, apolipoprotein-D adopts an eight-stranded β-barrel fold stabilised by two intramolecular disulphide bonds, with an adjacent α-helix. Crystallography studies of recombinant apolipoprotein-D demonstrated no major conformational changes upon progesterone binding. Amide hydrogen-deuterium exchange mass spectrometry (HDX-MS) reports structural changes of proteins in solution by monitoring exchange of amide hydrogens in the protein backbone with deuterium...
October 24, 2018: Protein Science: a Publication of the Protein Society
M Daniel Ricketts, Joseph Han, Mary Szurgot, Ronen Marmorstein
Epigenetic regulation of the chromatin landscape is often orchestrated through modulation of nucleosomes. Nucleosomes are composed of 2 copies each of the four core histones, H2A, H2B, H3 and H4, wrapped in ~150 bp of DNA. We focus this review on recent structural studies that further elucidate the mechanisms employed by macromolecular complexes to mediate histone modification and nucleosome assembly. Nucleosome assembly, spacing, and variant histone incorporation are coordinated by chromatin remodeler and histone chaperone complexes...
October 23, 2018: Protein Science: a Publication of the Protein Society
Viktoriya Syrovatkina, Xin-Yun Huang
Heterotrimeric G-proteins are cellular signal transducers. They mainly relay signals from G-protein-coupled receptors (GPCRs). GPCRs function as guanine nucleotide-exchange factors to active these G-proteins. Based on the sequence and functional similarities, these G-proteins are grouped into four subfamilies: Gs , Gi , Gq and G12/13 . The G12/13 subfamily consists of two members: G12 and G13 . G12/13 -mediated signaling pathways play pivotal roles in a variety of physiological processes, while aberrant regulation of this pathway has been identified in various human diseases...
October 21, 2018: Protein Science: a Publication of the Protein Society
Stephen B H Kent
Chemical synthesis is a well-established method for preparation in the research laboratory of multiple-tens-of-milligram amounts of correctly folded, high purity protein molecules. Chemically synthesized proteins enable a broad spectrum of novel protein science. Racemic mixtures consisting of D-protein and L-protein enantiomers facilitate crystallization and determination of protein structures by X-ray diffraction. D-Proteins enable the systematic development of unnatural mirror image protein molecules that bind with high affinity to natural protein targets...
October 21, 2018: Protein Science: a Publication of the Protein Society
Kazuhide Miyamoto, Yukari Taguchi, Kazuki Saito
Artificial RING fingers (ARFs) are created by transplanting active sites of RING fingers onto cross-brace structures. Human hydroxymethylglutaryl-coenzyme A reductase degradation protein 1 (HRD1) is involved in degradation of the endoplasmic reticulum (ER) proteins. HRD1 possesses the RING finger domain (HRD1_RING) that functions as a ubiquitin-ligating (E3) enzyme. Herein, we determined the solution structure of HRD1_RING using nuclear magnetic resonance (NMR). Moreover, using a metallochromic indicator, we determined the stoichiometry of zinc ions spectrophotometrically and found that HRD1_RING binds to two zinc atoms...
October 21, 2018: Protein Science: a Publication of the Protein Society
Tsehai A J Grell, Benjamin N Bell, Chi Nguyen, Daniel P Dowling, Nathan A Bruender, Vahe Bandarian, Catherine L Drennan
7-carboxy-7-deazaguanine synthase, QueE, catalyzes the radical mediated ring contraction of 6-carboxy-5,6,7,8-tetrahydropterin, forming the characteristic pyrrolopyrimidine core of all 7-deazaguanine natural products. QueE is a member of the S-adenosyl-L-methionine (AdoMet) radical enzyme superfamily, which harnesses the reactivity of radical intermediates to perform challenging chemical reactions. Members of the AdoMet radical enzyme superfamily utilize a canonical binding motif, a CX3 CXφC motif, to bind a [4Fe-4S] cluster and a partial (β/α)6 TIM barrel fold for the arrangement of AdoMet and substrates for catalysis...
October 19, 2018: Protein Science: a Publication of the Protein Society
Takushi Fujimoto, Kenji Inaba, Hiroshi Kadokura
Formation of a disulfide bond is a critical step in the folding of numerous secretory and membrane proteins and catalyzed in vivo. A variety of mechanisms and protein structures have evolved to catalyze oxidative protein folding. Those enzymes that directly interact with a folding protein to accelerate its oxidative folding are mostly thiol-disulfide oxidoreductases that belong to the thioredoxin superfamily. The enzymes of this class often use a CXXC active-site motif embedded in their thioredoxin-like fold to promote formation, isomerization, and reduction of a disulfide bond in their target proteins...
October 19, 2018: Protein Science: a Publication of the Protein Society
Pirom Chenprakhon, Thanyaporn Wongnate, Pimchai Chaiyen
Many flavoenzymes catalyze hydroxylation of aromatic compounds especially phenolic compounds have been isolated and characterized. These enzymes can be classified as either single-component or two-component flavin dependent hydroxylases (monooxygenases). The hydroxylation reactions catalyzed by the enzymes in this group are useful for modifying the biological properties of phenolic compounds. This review aims to provide an in-depth discussion of the current mechanistic understanding of representative flavin-dependent monooxygenases including 3-hydroxy-benzoate 4-hydroxylase (PHBH, a single-component hydroxylase), 3-hydroxyphenylacetate 4-hydroxylase (HPAH, a two-component hydroxylase) and other monooxygenases which catalyze reactions in addition to hydroxylation, including 2-methyl-3-hydroxypyridine-5-carboxylate oxygenase (MHPCO, a single-component enzyme that catalyzes aromatic-ring cleavage), and HadA monooxygenase (a two-component enzyme that catalyzes additional group elimination reaction)...
October 12, 2018: Protein Science: a Publication of the Protein Society
Polytimi S Dimitriou, Alexander I Denesyuk, Toru Nakayama, Mark S Johnson, Konstantin Denessiouk
The alpha/beta-hydrolases (ABH) are among the largest structural families of proteins that are found in nature. Although they vary in their sequence and function, the ABH enzymes use a similar acid-base-nucleophile catalytic mechanism to catalyze reactions on different substrates. Because ABH enzymes are biocatalysts with a wide range of potential applications, protein engineering has taken advantage of their catalytic versatility to develop enzymes with industrial applications. This study is a comprehensive analysis of 40 ABH enzyme families focusing on two identified substructures: the nucleophile zone and the oxyanion zone, which coordinate the catalytic nucleophile and the residues of the oxyanion hole, and independently reported as critical for the enzymatic activity...
October 12, 2018: Protein Science: a Publication of the Protein Society
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