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Protein Science: a Publication of the Protein Society

Zbigniew Dauter, Mariusz Jaskolski
Helical structures are prevalent in biology. In the PDB there are many examples where protein molecules are helically arranged, not only according to strict crystallographic screw axes, but also according to approximate non-crystallographic screws. The preponderance of such screws is rather striking as helical arrangements in crystals must preserve an integer number of subunits per turn, while intuition and simple packing arguments would seem to favor fractional helices. The article provides insights into such questions, based on stereochemistry, trigonometry and topology, and illustrates the findings with concrete PDB structures...
December 1, 2017: Protein Science: a Publication of the Protein Society
Xuejun C Zhang, Min Liu, Guangyuan Lu, Jie Heng
Multidrug resistance (MDR) presents a growing challenge to global public health. Drug extrusion transporters play a critical part in MDR; thus, their mechanisms of substrate recognition are being studied in great detail. In this work, we review common structural features of key transporters involved in MDR. Based on our membrane potential-driving hypothesis, we propose a general energy-coupling mechanism for secondary-active antiporters. This putative mechanism provides a common framework for understanding poly-specificity of most - if not all - MDR transporters...
November 30, 2017: Protein Science: a Publication of the Protein Society
Kim K C Li, Bess L Chau, Kevin A W Lee
The FET sub-family (FUS/TLS, EWS, TAF15) of RNA-binding proteins have remarkably similar overall structure but diverse biological and pathological roles. The molecular basis for FET protein specialisation is largely unknown. Gly-Arg-Rich regions (RGG-boxes) within FET proteins are targets for methylation by Protein-Arginine-Methyl-Transferase-1 (PRMT1) and substrate capture is thought to involve electrostatic attraction between positively charged polyRGG substrates and negatively charged surface channels of PRMT1...
November 30, 2017: Protein Science: a Publication of the Protein Society
Martina Buonanno, Mariangela Coppola, Ilaria Di Lelio, Donata Molisso, Marilisa Leone, Francesco Pennacchio, Emma Langella, Rosa Rao, Simona Maria Monti
Prosystemin, originally isolated from Lycopersicon esculentum, is a tomato pro-hormone of 200 aminoacid residues which releases a bioactive peptide of 18 aminoacids called Systemin. This signaling peptide is involved in the activation of defense genes in solanaceous plants in response to herbivore feeding damage. Using biochemical, biophysical and bioinformatics approaches we characterized Prosystemin, showing that it is an intrinsically disordered protein possessing a few secondary structure elements within the sequence...
November 23, 2017: Protein Science: a Publication of the Protein Society
Sam L Ivry, Nicole O Meyer, Michael B Winter, Markus F Bohn, Giselle M Knudsen, Anthony J O'Donoghue, Charles S Craik
Enzymes that modify the proteome, referred to as post-translational modifying (PTM) enzymes, are central regulators of cellular signaling. Determining the substrate specificity of PTM enzymes is a critical step in unraveling their biological functions both in normal physiological processes and in disease states. Advances in peptide chemistry over the last century have enabled the rapid generation of peptide libraries for querying substrate recognition by PTM enzymes. In this review, we highlight various peptide-based approaches for analysis of PTM enzyme substrate specificity...
November 23, 2017: Protein Science: a Publication of the Protein Society
Bart van Beusekom, Wouter G Touw, Mahidhar Tatineni, Sandeep Somani, Gunaretnam Rajagopal, Jinquan Luo, Gary L Gilliland, Anastassis Perrakis, Robbie P Joosten
The Protein Data Bank (PDB) is the global archive for structural information on macromolecules, and a popular resource for researchers, teachers and students, amassing more than one million unique users each year. Crystallographic structure models in the PDB (more than 100,000 entries) are optimized against the crystal diffraction data and geometrical restraints. This process of crystallographic refinement typically ignored hydrogen bond (H-bond) distances as a source of information. However, H-bond restraints can improve structures at low resolution where diffraction data are limited...
November 23, 2017: Protein Science: a Publication of the Protein Society
Flavia Squeglia, Alessia Ruggiero, Alfonso De Simone, Rita Berisio
Adherence, colonization, and survival of mycobacteria in host cells require surface adhesins, which are attractive pharmacotherapeutic targets. A large arsenal of pilus and non-pilus adhesins have been identified in mycobacteria. These adhesins are capable of interacting with host cells, including macrophages and epithelial cells and are essential to microbial pathogenesis. In the last decade, several structures of mycobacterial adhesins responsible for adhesion to either macrophages or extra cellular matrix proteins have been elucidated...
November 15, 2017: Protein Science: a Publication of the Protein Society
Kelsey M Kean, Joseph J Porter, Ryan A Mehl, P Andrew Karplus
Carbonic anhydrase is an enzyme of interest for many biotechnological developments including carbon sequestration. These applications often require harsh conditions, so there is a need for the development of thermostable variants. One of the most thermostable human carbonic anhydrase II variants (HCAIIts) was patented in 2006. Here, we report the ultra-high resolution crystal structure of HCAIIts. The structural changes seen are consistent with each of the six mutations involved acting largely independently and variously resulting in increased H-bonding, improved packing, and reduced side chain entropy loss upon folding to yield the increased stability...
November 15, 2017: Protein Science: a Publication of the Protein Society
Jason Harris, Maria Shadrina, Carlos Oliver, Jackie Vogel, Anthony Mittermaier
Tubulins are an ancient family of eukaryotic proteins characterized by an amino-terminal globular domain and disordered carboxyl terminus. These carboxyl termini play important roles in modulating the behavior of microtubules in living cells. However, the atomic-level basis of their function is not well understood. These regions contain multiple acidic residues and their overall charges are modulated in vivo by post-translational modifications, e.g. phosphorylation. In this study, we describe an application of NMR and computer Monte Carlo simulations to investigate how the modification of local charge alters the conformational sampling of the γ-tubulin carboxyl terminus...
November 11, 2017: Protein Science: a Publication of the Protein Society
Petr Muller, Juliana M Chan, Oliver Simoncik, Miroslav Fojta, David P Lane, Ted Hupp, Borivoj Vojtesek
P53 is a tetrameric protein with a thermodynamically unstable DNA-binding domain flanked by intrinsically disordered regulatory domains that control its activity. The unstable and disordered segments of p53 allow high flexibility as it interacts with binding partners and permits a rapid on/off switch to control its function. The p53 tetramer can exist in multiple conformational states, any of which can be stabilized by a particular modification. Here, we apply the allostery model to p53 to ask whether evidence can be found that the "activating" C-terminal phosphorylation of p53 stabilizes a specific conformation of the protein in the absence of DNA...
November 10, 2017: Protein Science: a Publication of the Protein Society
Jan Abendroth, Andrew Frando, Isabelle Q Phan, Bart L Staker, Peter J Myler, Thomas E Edwards, Christoph Grundner
The genome of the human pathogen Mycobacterium tuberculosis (Mtb) encodes ∼4,400 proteins, but one third of them have unknown functions. We solved the crystal structure of Rv3651, a hypothetical protein with no discernible similarity to proteins with known function. Rv3651 has a three-domain architecture that combines one cGMP-specific phosphodiesterases, adenylyl cyclases and FhlA (GAF) domain and two Per-ARNT-Sim (PAS) domains. GAF and PAS domains are typically sensor domains that are linked to signaling effector molecules...
November 9, 2017: Protein Science: a Publication of the Protein Society
Daphne A C Stapels, Jordan L Woehl, Fin J Milder, Angelino T Tromp, Aernoud A van Batenburg, Wilco C de Graaf, Samuel C Broll, Natalie M White, Suzan H M Rooijakkers, Brian V Geisbrecht
Neutrophils contain high levels of chymotrypsin-like serine proteases (NSPs) within their azurophilic granules that have a multitude of functions within the immune system. In response, the pathogen Staphylococcus aureus has evolved three potent inhibitors (Eap, EapH1, and EapH2) that protect the bacterium as well as several of its secreted virulence factors from the degradative action of NSPs. We previously showed that these so-called EAP domain proteins represent a novel class of NSP inhibitors characterized by a non-covalent inhibitory mechanism and a distinct target specificity profile...
November 7, 2017: Protein Science: a Publication of the Protein Society
Thu Ly, Inna Krieger, Dmitri Tolkatchev, Cheyenna Krone, Timothy Moural, Fadel A Samatey, ChulHee Kang, Alla S Kostyukova
The missense mutation R21H in striated muscle tropomyosin is associated with hypertrophic cardiomyopathy, a genetic cardiac disease and a leading cause of sudden cardiac death in young people. Tropomyosin adopts conformation of a coiled-coil that is critical for regulation of muscle contraction. In this study, we investigated the effects of the R21H mutation on the coiled-coil structure of tropomyosin and its interactions with its binding partners, tropomodulin and leiomodin. Using circular dichroism and isothermal titration calorimetry, we found that the mutation profoundly destabilized the structural integrity of αTM1a1-28 Zip, a chimeric peptide containing the first 28 residues of tropomyosin...
November 6, 2017: Protein Science: a Publication of the Protein Society
Mary Ashley Rimmer, Owen W Nadeau, Antonio Artigues, Gerald M Carlson
In the tightly regulated glycogenolysis cascade, the breakdown of glycogen to glucose-1-phosphate, phosphorylase kinase (PhK) plays a key role in the regulating the activity of glycogen phosphorylase. PhK is a 1.3 MDa hexadecamer, with four copies each of four different subunits (α, β, γ and δ), making the study of its structure challenging. Using hydrogen-deuterium exchange, we have analyzed the regulatory β subunit and the catalytic γ subunit in the context of the intact non-activated PhK complex, to study the structure of these subunits and identify regions of surface exposure...
November 3, 2017: Protein Science: a Publication of the Protein Society
Mary Ashley Rimmer, Owen W Nadeau, Jianyi Yang, Antonio Artigues, Yang Zhang, Gerald M Carlson
Phosphorylase kinase (PhK), a 1.3 MDa regulatory enzyme complex in the glycogenolysis cascade, has four copies each of four subunits, (αβγδ)4 , and 325 kDa of unique sequence (the mass of an αβγδ protomer). The α, β and δ subunits are regulatory, and contain allosteric activation sites that stimulate the activity of the catalytic γ subunit in response to diverse signaling molecules. Due to its size and complexity, no high resolution structures have been solved for the intact complex or its regulatory α and β subunits...
November 3, 2017: Protein Science: a Publication of the Protein Society
Yu-Ming M Huang, Gary A Huber, Nuo Wang, Shelley D Minteer, J Andrew McCammon
Malate dehydrogenase (MDH) and citrate synthase (CS) are two pacemaking enzymes involved in the tricarboxylic acid (TCA) cycle. Oxaloacetate (OAA) molecules are the intermediate substrates that are transferred from the MDH to CS to carry out sequential catalysis. It is known that, to achieve a high flux of intermediate transport and reduce the probability of substrate leaking, a MDH-CS metabolon forms to enhance the OAA substrate channeling. In this study, we aim to understand the OAA channeling within possible MDH-CS metabolons that have different structural orientations in their complexes...
November 2, 2017: Protein Science: a Publication of the Protein Society
Jannik Nedergaard Pedersen, Jan Skov Pedersen, Daniel E Otzen
Proteins and lipids can form complexes called liprotides, in which the partially denatured protein forms a shell encasing a lipid core. This effectively stabilizes a lipid micelle in an aqueous solvent and suggests that liprotides may provide a suitable vessel for membrane proteins. Accordingly we have investigated if liprotides consisting of α-lactalbumin and oleate could aid folding of four different outer membrane proteins (OMPs) tOmpA, PagP, BamA and OmpF. tOmpA was able to fold in the presence of the liprotide, and folding did not occur if only oleate or α-lactalbumin were added...
November 1, 2017: Protein Science: a Publication of the Protein Society
Anabel Rodriguez, Gabriel Wright, Scott Emrich, Patricia L Clark
Most amino acids can be encoded by more than one synonymous codon, but these are rarely used with equal frequency. In many coding sequences the usage patterns of rare versus common synonymous codons is non-random and under selection. Moreover, synonymous substitutions that alter these patterns can have a substantial impact on the folding efficiency of the encoded protein. This has ignited broad interest in exploring synonymous codon usage patterns. For many protein chemists, biophysicists and structural biologists, the primary motivation for codon analysis is identifying and preserving usage patterns most likely to impact high-yield production of functional proteins...
November 1, 2017: Protein Science: a Publication of the Protein Society
Amanda M Duran, Jens Meiler
Computational membrane protein design is challenging due to the small number of high-resolution structures available to elucidate the physical basis of membrane protein structure, multiple functionally important conformational states, and a limited number of high-throughput biophysical assays to monitor function. However, structural determination of membrane proteins has made tremendous progress in the past years. Concurrently the field of soluble computational design has made impressive inroads. These developments allow us to tackle the formidable challenge of designing functional membrane proteins...
November 1, 2017: Protein Science: a Publication of the Protein Society
Liam M Longo, Yuan Gao, Connie A Tenorio, Gan Wang, Anant K Paravastu, Michael Blaber
An efficient protein folding pathway leading to target structure, and the avoidance of aggregation, is essential to protein evolution and de novo design; however, design details to achieve efficient folding and avoid aggregation are poorly understood. We report characterization of the thermally-induced aggregate of fibroblast growth factor-1 (FGF-1), a small globular protein, by solid-state NMR. NMR spectra are consistent with residual structure in the aggregate and provide evidence of a structured region that corresponds to the region of the folding nucleus...
October 27, 2017: Protein Science: a Publication of the Protein Society
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