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Protein Science: a Publication of the Protein Society

Rebekka Wild, Michael Hothorn
Obtaining well-ordered crystals remains a significant challenge in protein X-ray crystallography. Carrier-driven crystallization can facilitate crystal formation and structure solution of difficult target proteins. We obtained crystals of the small and highly flexible SPX domain from the yeast vacuolar transporter chaperone 4 (Vtc4) when fused to a C-terminal, non-cleavable macro tag derived from human histone macroH2A1.1. Initial crystals diffracted to 3.3 Å resolution. Reductive protein methylation of the fusion protein yielded a new crystal form diffracting to 2...
October 24, 2016: Protein Science: a Publication of the Protein Society
Kathleen M Clark, Jermaine L Jenkins, Nadia Fedoriw, Mark E Dumont
The function and localization of proteins and peptides containing C-terminal "CaaX" (Cys-aliphatic-aliphatic-anything) sequence motifs are modulated by post-translational attachment of isoprenyl groups to the cysteine sulfhydryl, followed by proteolytic cleavage of the aaX amino acids. The zinc metalloprotease ZMPSTE24 is one of two enzymes known to catalyze this cleavage. The only identified target of mammalian ZMPSTE24 is prelamin A, the precursor to the nuclear scaffold protein lamin A. ZMPSTE24 also cleaves prelamin A at a second site 15 residues upstream from the CaaX site...
October 24, 2016: Protein Science: a Publication of the Protein Society
Yang Yu, Igor Petrik, Kelly N Chacón, Parisa Hosseinzadeh, Honghui Chen, Ninian J Blackburn, Yi Lu
Type 1 copper (T1Cu) proteins are electron transfer (ET) proteins involved in many important biological processes. While the effects of changing primary and secondary coordination spheres in the T1Cu ET function have been extensively studied, no report has explored the effect of the overall protein structural perturbation on active site configuration or reduction potential of the protein, even though the protein scaffold has been proposed to play a critical role in enforcing the entatic or "rack-induced" state for ET functions...
October 19, 2016: Protein Science: a Publication of the Protein Society
Zheng Liu, Cristina Gutierrez-Vargas, Jia Wei, Robert A Grassucci, Noel Espina, Susan Madison-Antenucci, Liang Tong, Joachim Frank
With the advance of new instruments and algorithms, and the accumulation of experience over decades, single-particle cryo-EM has become a pivotal part of structural biology. Recently, we determined the structure of a eukaryotic ribosome at 2.5 Å for the large subunit. The ribosome was derived from Trypanosoma cruzi, the protozoan pathogen of Chagas disease. The high-resolution density map allowed us to discern a large number of unprecedented details including rRNA modifications, water molecules, and ions such as Mg(2+) and Zn(2+) ...
October 17, 2016: Protein Science: a Publication of the Protein Society
Joseph R Sachleben, Aashish N Adhikari, Grzegorz Gawlak, Robert J Hoey, Gaohua Liu, Andrzej Joachimiak, Gaetano T Montelione, Tobin R Sosnick, Shohei Koide
We determined the NMR structure of a highly aromatic (13%) protein of unknown function, Aq1974 from Aquifex aeolicus. The unusual sequence of this protein has a tryptophan content 5 times the normal (six tryptophan residues of 114 or 5.2% while the average tryptophan content is 1.0%) with the tryptophans occurring in a WXW motif. It has no detectable sequence homology with known protein structures. Although its NMR spectrum suggested that the protein was rich in β-sheet, upon resonance assignment and solution structure determination, the protein was found to be primarily α-helical with a small two-stranded β-sheet with a novel fold that we have termed an Aromatic Claw...
October 17, 2016: Protein Science: a Publication of the Protein Society
Mikko Laitaoja, Sari Isoniemi, Jarkko Valjakka, Istvan M Mándity, Janne Jänis
Small zinc finger (ZnF) motifs are promising molecular scaffolds for protein design owing to their structural robustness and versatility. Moreover, their characterization provides important insights into protein folding in general. ZnF motifs usually possess an exceptional specificity and high affinity towards Zn(II) ion to drive folding. While the Zn(II) ion is canonically coordinated by two cysteine and two histidine residues, many other coordination spheres also exist in small ZnFs, all having four amino acid ligands...
October 17, 2016: Protein Science: a Publication of the Protein Society
Martín Carballo-Pacheco, Birgit Strodel
Intrinsically disordered proteins are essential for biological processes such as cell signalling, but are also associated to devastating diseases including Alzheimers disease, Parkinsons disease or type II diabetes. Because of their lack of a stable threedimensional structure, molecular dynamics simulations are often used to obtain atomistic details that cannot be observed experimentally. The applicability of molecular dynamics simulations depends on the accuracy of the force field chosen to represent the underlying free energy surface of the system...
October 11, 2016: Protein Science: a Publication of the Protein Society
Douglas Marcotte, Mia Rushe, Robert M Arduini, Christine Lukacs, Kateri Atkins, Xin Sun, Kevin Little, Michael Cullivan, Murugan Paramasivam, Thomas A Patterson, Thomas Hesson, Timothy D McKee, Tricia L May-Dracka, Zhili Xin, Andrea Bertolotti-Ciarlet, Govinda R Bhisetti, Joseph P Lyssikatos, Laura F Silvian
Germinal-center kinase-like kinase (GLK, Map4k3), a GCK-I family kinase, plays multiple roles in regulating apoptosis, amino acid sensing, and immune signaling. We describe here the crystal structure of an activation loop mutant of GLK kinase domain bound to an inhibitor. The structure reveals a weakly associated, activation-loop swapped dimer with more than 20 amino acids of ordered density at the carboxy-terminus. This C-terminal PEST region binds intermolecularly to the hydrophobic groove of the N-terminal domain of a neighboring molecule...
October 11, 2016: Protein Science: a Publication of the Protein Society
Lingyun Wang, Ji-Bin Peng
Interaction between the acidic motif (AM) of protein kinase WNK4 and the Kelch domain of KLHL3 are involved in the pathogenesis of pseudohypoaldosteronism type II, a hereditary form of hypertension. This interaction is disrupted by some disease-causing mutations in either WNK4 or KLHL3, or by angiotensin II- and insulin-induced phosphorylation of KLHL3 at serine 433, which is also a site frequently mutated in patients. However, the mechanism by which this phosphorylation disrupts the interaction is unclear...
October 11, 2016: Protein Science: a Publication of the Protein Society
Anjneya Takshak, Tanushree Roy, Parag Tandaiya, Ambarish Kunwar
Motor proteins are essential components of intracellular transport inside eukaryotic cells. These protein molecules use chemical energy obtained from hydrolysis of ATP to produce mechanical forces required for transporting cargos inside cells, from one location to another, in a directed manner. Of these motors, cytoplasmic dynein is structurally more complex than other motor proteins involved in intracellular transport, as it shows force and fuel (ATP) concentration dependent step-size. Cytoplasmic dynein motors are known to work in a team during cargo transport and force generation...
October 11, 2016: Protein Science: a Publication of the Protein Society
Nicolas Coudray, Sean L Seyler, Ralph Lasala, Zhening Zhang, Kathy M Clark, Mark E Dumont, Alexis Rohou, Oliver Beckstein, David L Stokes
Bor1p is a secondary transporter in yeast that is responsible for boron transport. Bor1p belongs to the SLC4 family which controls bicarbonate exchange and pH regulation in animals as well as borate uptake in plants. The SLC4 family is more distantly related to members of the Amino acid-Polyamine-organoCation (APC) superfamily, which includes well studied transporters such as LeuT, Mhp1, AdiC, vSGLT, UraA, SLC26Dg. Their mechanism generally involves relative movements of two domains: a core domain that binds substrate and a gate domain that in many cases mediates dimerization...
October 7, 2016: Protein Science: a Publication of the Protein Society
Yoshimasa Takizawa, Elad Binshtein, Amanda L Erwin, Tasia M Pyburn, Kathleen F Mittendorf, Melanie D Ohi
Single-particle cryo-electron microscopy (EM) is currently gaining attention for the ability to calculate structures that reach sub-5 Å resolutions; however, the technique is more than just an alternative approach to X-ray crystallography. Molecular machines work via dynamic conformational changes, making structural flexibility the hallmark of function. While the dynamic regions in molecules are essential, they are also the most challenging to structurally characterize. Single-particle EM has the distinct advantage of being able to directly visualize purified molecules without the formation of ordered arrays of molecules locked into identical conformations...
October 6, 2016: Protein Science: a Publication of the Protein Society
Jimin Wang, Peter B Moore
The images of flash-frozen biological macromolecules produced by cryo-electron microscopy (EM) can be used to generate accurate, three-dimensional, electric potential maps for these molecules that resemble X-ray-derived electron density maps. However, unlike electron density maps, electric potential maps can include negative features that might for example represent the negatively charged, backbone phosphate groups of nucleic acids or protein carboxylate side chains, which can complicate their interpretation...
October 5, 2016: Protein Science: a Publication of the Protein Society
Peter Haberz, Munehito Arai, Maria A Martinez-Yamout, H Jane Dyson, Peter E Wright
Many viruses deregulate the cell and force transcription of viral genes by competing with cellular proteins for binding to the transcriptional co-activators CREB-binding protein (CBP) and p300. Through its interactions with CBP/p300 and the retinoblastoma protein, the adenovirus (AdV) early region 1A (E1A) oncoprotein hijacks the cell cycle and, in rodents, transforms the cell; the mechanistic and structural basis for these effects remain unclear. In this study we compare the affinity of protein constructs from the E1A proteins from two adenovirus serotypes, non-oncogenic AdV5 and highly oncogenic AdV12, for binding to the nuclear receptor coactivator binding domain (NCBD) of CBP...
October 4, 2016: Protein Science: a Publication of the Protein Society
Norbert Schormann, Natalia Zhukovskaya, Gregory Bedwell, Manunya Nuth, Richard Gillilan, Peter E Prevelige, Robert P Ricciardi, Surajit Banerjee, Debasish Chattopadhyay
Uracil-DNA glycosylases are ubiquitous enzymes, which play a key role repairing damages in DNA and in maintaining genomic integrity by catalyzing the first step in the base excision repair pathway. Within the superfamily of uracil-DNA glycosylases family I enzymes or UNGs are specific for recognizing and removing uracil from DNA. These enzymes feature conserved structural folds, active site residues and use common motifs for DNA binding, uracil recognition and catalysis. Within this family the enzymes of poxviruses are unique and most remarkable in terms of amino acid sequences, characteristic motifs and more importantly for their novel non-enzymatic function in DNA replication...
September 29, 2016: Protein Science: a Publication of the Protein Society
Xingqing Xiao, Binwu Zhao, Paul F Agris, Carol K Hall
In this paper, we investigate the ability of our computationally-designed peptide, Pept10 (PNWNGNRWLNNCLRG), to recognize the anticodon stem and loop (ASL) domain of the hypermodified tRNA(Lys3) (mcm(5) s(2) U34 ,ms(2) t(6) A37 ), a reverse transcription primer of HIV replication. Five other ASLs, the singly modified ASL(Lys3) (ms(2) t(6) A37 ), ASL(Lys3) (s(2) U34 ), ASL(Lys3) (Ψ39 ), ASL(Lys1,2) (t(6) A37 ), and ASL(Glu) (s(2) U34 ), were used as decoys. Explicit-solvent atomistic molecular dynamics simulations were performed to examine the process of binding of Pept10 with the target ASL(Lys3) (mcm(5) s(2) U34 ,ms(2) t(6) A37 ) and the decoy ASLs...
September 28, 2016: Protein Science: a Publication of the Protein Society
Howard C Berg
A short review is given of recent work showing that the flagellar rotary motor of the bacterium Escherichia coli remodels to match its operating point (the fraction of time that it spins clockwise) to the requirements of the chemotaxis signaling network, and to provide the torque necessary to operate at different viscous loads.
September 28, 2016: Protein Science: a Publication of the Protein Society
Raghavendran Ramaswamy, Sarah Goomeshi Nobary, Brett A Eyford, Terry W Pearson, Martin J Boulanger
African trypanosomiasis, caused by parasites of the genus Trypanosoma, is a complex of devastating vector-borne diseases of humans and livestock in sub-Saharan Africa. Central to the pathogenesis of African trypanosomes is their transmission by the arthropod vector, Glossina spp. (tsetse fly). Intriguingly, the efficiency of parasite transmission through the vector is reduced following depletion of Trypanosoma brucei Procyclic-Specific Surface Antigen-2 (TbPSSA-2). To investigate the underlying molecular mechanism of TbPSSA-2, we determined the crystal structures of its ectodomain and that of its homolog T...
September 27, 2016: Protein Science: a Publication of the Protein Society
Montserrat Samsó
Signal transduction by the ryanodine receptor (RyR) is essential in many excitable cells including all striated contractile cells and some types of neurons. While its transmembrane domain is a classic tetrameric, six-transmembrane cation channel, the cytoplasmic domain is uniquely large and complex, hosting a multiplicity of specialized domains. The overall outline and substructure readily recognizable by electron microscopy make RyR a geometrically well-behaved specimen. Hence, for the last two decades, the 3D structural study of the RyR has tracked closely the technological advances in electron microscopy, cryo-electron microscopy (cryoEM), and computerized 3D reconstruction...
September 27, 2016: Protein Science: a Publication of the Protein Society
Marine Bacchi, Magali Jullian, Serena Sirigu, Benjamin Fould, Tiphaine Huet, Lisa Bruyand, Mathias Antoine, Laurent Vuillard, Luisa Ronga, Leonard M G Chavas, Olivier Nosjean, Gilles Ferry, Karine Puget, Jean A Boutin
Synthetic biology (or chemical biology) is a growing field to which the chemical synthesis of proteins, particularly enzymes, makes a fundamental contribution. However, the chemical synthesis of catalytically active proteins (enzymes) remains poorly documented because it is difficult to obtain enough material for biochemical experiments. We chose calstabin, a 107-amino-acid proline isomerase, as a model. We synthesized the enzyme using the native chemical ligation approach and obtained several tens of milligrams...
September 27, 2016: Protein Science: a Publication of the Protein Society
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