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Miguel Arbesú, Mariano Maffei, Tiago N Cordeiro, João M C Teixeira, Yolanda Pérez, Pau Bernadó, Serge Roche, Miquel Pons
The N-terminal regulatory region of c-Src including the SH4, Unique, and SH3 domains adopts a compact, yet highly dynamic, structure that can be described as an intramolecular fuzzy complex. Most of the long-range interactions within the Unique domain are also observed in constructs lacking the structured SH3, indicating a considerable degree of preorganization of the disordered Unique domain. Here we report that members of the Src family of kinases (SFK) share well-conserved sequence features involving aromatic residues in their Unique domains...
March 16, 2017: Structure
Veronica Salmaso, Mattia Sturlese, Alberto Cuzzolin, Stefano Moro
Peptides have gained increased interest as therapeutic agents during recent years. The high specificity and relatively low toxicity of peptide drugs derive from their extremely tight binding to their targets. Indeed, understanding the molecular mechanism of protein-peptide recognition has important implications in the fields of biology, medicine, and pharmaceutical sciences. Even if crystallography and nuclear magnetic resonance are offering valuable atomic insights into the assembling of the protein-peptide complexes, the mechanism of their recognition and binding events remains largely unclear...
March 10, 2017: Structure
Mohammad Kawsar Manik, Huiseon Yang, Junsen Tong, Young Jun Im
Yeast Osh1 belongs to the oxysterol-binding protein (OSBP) family of proteins and contains multiple targeting modules optimized for lipid transport at the nucleus-vacuole junction (NVJ). The key determinants for NVJ targeting and the role of Osh1 at NVJs have remained elusive because of unknown lipid specificities. In this study, we determined the structures of the ankyrin repeat domain (ANK), and OSBP-related domain (ORD) of Osh1, in complex with Nvj1 and ergosterol, respectively. The Osh1 ANK forms a unique bi-lobed structure that recognizes a cytosolic helical segment of Nvj1...
March 10, 2017: Structure
Zhen-Lu Li, Matthias Buck
The structural, dynamical, and functional characterization of the small GTPase K-Ras has become a research area of intense focus due to its high occurrence in human cancers. Ras proteins are only fully functional when they interact with the plasma membrane. Here we present all-atom molecular dynamics simulations (totaling 5.8 μs) to investigate the K-Ras4A protein at membranes that contain anionic lipids (phosphatidyl serine or phosphatidylinositol bisphosphate). We find that similarly to the homologous and highly studied K-Ras4B, K-Ras4A prefers a few distinct orientations at the membrane...
March 9, 2017: Structure
Brianna J Klein, Johayra Simithy, Xiaolu Wang, JaeWoo Ahn, Forest H Andrews, Yi Zhang, Jacques Côté, Xiaobing Shi, Benjamin A Garcia, Tatiana G Kutateladze
The monocytic leukemia zinc-finger protein-related factor (MORF) is a transcriptional coactivator and a catalytic subunit of the lysine acetyltransferase complex implicated in cancer and developmental diseases. We have previously shown that the double plant homeodomain finger (DPF) of MORF is capable of binding to acetylated histone H3. Here we demonstrate that the DPF of MORF recognizes many newly identified acylation marks. The mass spectrometry study provides comprehensive analysis of H3K14 acylation states in vitro and in vivo...
March 9, 2017: Structure
Katsuhiko Kamada, Masayuki Su'etsugu, Hiraku Takada, Makoto Miyata, Tatsuya Hirano
The SMC-ScpAB complex plays a crucial role in chromosome organization and segregation in many bacteria. It is composed of a V-shaped SMC dimer and an ScpAB subcomplex that bridges the two Structural Maintenance of Chromosomes (SMC) head domains. Despite its functional significance, the mechanistic details of SMC-ScpAB remain obscure. Here we provide evidence that ATP-dependent head-head engagement induces a lever movement of the SMC neck region, which might help to separate juxtaposed coiled-coil arms. Binding of the ScpA N-terminal domain (NTD) to the SMC neck region is negatively regulated by the ScpB C-terminal domain...
March 7, 2017: Structure
Xiangsong Feng, Ziao Fu, Sandip Kaledhonkar, Yuan Jia, Binita Shah, Amy Jin, Zheng Liu, Ming Sun, Bo Chen, Robert A Grassucci, Yukun Ren, Hongyuan Jiang, Joachim Frank, Qiao Lin
We describe a spraying-plunging method for preparing cryoelectron microscopy (cryo-EM) grids with vitreous ice of controllable, highly consistent thickness using a microfluidic device. The new polydimethylsiloxane (PDMS)-based sprayer was tested with apoferritin. We demonstrate that the structure can be solved to high resolution with this method of sample preparation. Besides replacing the conventional pipetting-blotting-plunging method, one of many potential applications of the new sprayer is in time-resolved cryo-EM, as part of a PDMS-based microfluidic reaction channel to study short-lived intermediates on the timescale of 10-1,000 ms...
March 6, 2017: Structure
Lyman Monroe, Genki Terashi, Daisuke Kihara
An increasing number of biomolecular structures are solved by electron microscopy (EM). However, the quality of structure models determined from EM maps vary substantially. To understand to what extent structure models are supported by information embedded in EM maps, we used two computational structure refinement methods to examine how much structures can be refined using a dataset of 49 maps with accompanying structure models. The extent of structure modification as well as the disagreement between refinement models produced by the two computational methods scaled inversely with the global and the local map resolutions...
March 2, 2017: Structure
Jianchao Li, Yiyun Chen, Yisong Deng, Ilona Christy Unarta, Qing Lu, Xuhui Huang, Mingjie Zhang
Several unconventional myosins contain a highly charged single α helix (SAH) immediately following the calmodulin (CaM) binding IQ motifs, functioning to extend lever arms of these myosins. How such SAH is connected to the IQ motifs and whether the conformation of the IQ motifs-SAH segments are regulated by Ca(2+) fluctuations are not known. Here, we demonstrate by solving its crystal structure that the predicted SAH of myosin VIIa (Myo7a) forms a stable SAH. The structure of Myo7a IQ5-SAH segment in complex with apo-CaM reveals that the SAH sequence can extend the length of the Myo7a lever arm...
February 24, 2017: Structure
Martin Zacharias
In this issue of Structure, Greener et al. (2017) describe a new computational approach to generate conformational ensembles of proteins based on two experimental input structures. The method shows promise for rapidly predicting global protein flexibility and for the identification of putative binding sites for allosteric effectors on proteins.
March 7, 2017: Structure
Jennifer Huen, Chia-Liang Lin, Bagher Golzarroshan, Wan-Li Yi, Wei-Zen Yang, Hanna S Yuan
CshA is a dimeric DEAD-box helicase that cooperates with ribonucleases for mRNA turnover. The molecular mechanism for how a dimeric DEAD-box helicase aids in RNA decay remains unknown. Here, we report the crystal structure and small-angle X-ray scattering solution structure of the CshA from Geobacillus stearothermophilus. In contrast to typical monomeric DEAD-box helicases, CshA is exclusively a dimeric protein with the RecA-like domains of each protomer forming a V-shaped structure. We show that the C-terminal domains protruding outward from the tip of the V-shaped structure is critical for mediating strong RNA binding and is crucial for efficient RNA-dependent ATP hydrolysis...
March 7, 2017: Structure
Robert E Powers, Rachelle Gaudet, Marcos Sotomayor
Tip links of the inner ear are protein filaments essential for hearing and balance. Two atypical cadherins, cadherin-23 and protocadherin-15, interact in a Ca(2+)-dependent manner to form tip links. The largely unknown structure and mechanics of these proteins are integral to understanding how tip links pull on ion channels to initiate sensory perception. Protocadherin-15 has 11 extracellular cadherin (EC) repeats. Its EC3-4 linker lacks several of the canonical Ca(2+)-binding residues, and contains an aspartate-to-alanine polymorphism (D414A) under positive selection in East Asian populations...
March 7, 2017: Structure
Zhaoyong Xi, Matthew J Whitley, Angela M Gronenborn
βγ-Crystallins are long-lived eye lens proteins that are crucial for lens transparency and refractive power. Each βγ-crystallin comprises two homologous domains, which are connected by a short linker. γ-Crystallins are monomeric, while β-crystallins crystallize as dimers and multimers. In the crystal, human βB2-crystallin is a domain-swapped dimer while the N-terminally truncated βB1-crystallin forms a face-en-face dimer. Combining and integrating data from multi-angle light scattering, nuclear magnetic resonance, and small-angle X-ray scattering of full-length and terminally truncated human βB2-crystallin in solution, we show that both these βB2-crystallin proteins are dimeric, possess C2 symmetry, and are more compact than domain-swapped dimers...
March 7, 2017: Structure
Chenghua Shao, Huanwang Yang, John D Westbrook, Jasmine Y Young, Christine Zardecki, Stephen K Burley
Following deployment of an augmented validation system by the Worldwide Protein Data Bank (wwPDB) partnership, the quality of crystal structures entering the PDB has improved. Of significance are improvements in quality measures now prominently displayed in the wwPDB validation report. Comparisons of PDB depositions made before and after introduction of the new reporting system show improvements in quality measures relating to pairwise atom-atom clashes, side-chain torsion angle rotamers, and local agreement between the atomic coordinate structure model and experimental electron density data...
March 7, 2017: Structure
Kala Bharath Pilla, Gottfried Otting, Thomas Huber
Computational and nuclear magnetic resonance hybrid approaches provide efficient tools for 3D structure determination of small proteins, but currently available algorithms struggle to perform with larger proteins. Here we demonstrate a new computational algorithm that assembles the 3D structure of a protein from its constituent super-secondary structural motifs (Smotifs) with the help of pseudocontact shift (PCS) restraints for backbone amide protons, where the PCSs are produced from different metal centers...
March 7, 2017: Structure
Jacob L W Morgan, Justin F Acheson, Jochen Zimmer
Type-1 secretion systems (T1SSs) represent a widespread mode of protein secretion across the cell envelope in Gram-negative bacteria. The T1SS is composed of an inner-membrane ABC transporter, a periplasmic membrane-fusion protein, and an outer-membrane porin. These three components assemble into a complex spanning both membranes and providing a conduit for the translocation of unfolded polypeptides. We show that ATP hydrolysis and assembly of the entire T1SS complex is necessary for protein secretion. Furthermore, we present a 3...
March 7, 2017: Structure
Jasmine Y Young, John D Westbrook, Zukang Feng, Raul Sala, Ezra Peisach, Thomas J Oldfield, Sanchayita Sen, Aleksandras Gutmanas, David R Armstrong, John M Berrisford, Li Chen, Minyu Chen, Luigi Di Costanzo, Dimitris Dimitropoulos, Guanghua Gao, Sutapa Ghosh, Swanand Gore, Vladimir Guranovic, Pieter M S Hendrickx, Brian P Hudson, Reiko Igarashi, Yasuyo Ikegawa, Naohiro Kobayashi, Catherine L Lawson, Yuhe Liang, Steve Mading, Lora Mak, M Saqib Mir, Abhik Mukhopadhyay, Ardan Patwardhan, Irina Persikova, Luana Rinaldi, Eduardo Sanz-Garcia, Monica R Sekharan, Chenghua Shao, G Jawahar Swaminathan, Lihua Tan, Eldon L Ulrich, Glen van Ginkel, Reiko Yamashita, Huanwang Yang, Marina A Zhuravleva, Martha Quesada, Gerard J Kleywegt, Helen M Berman, John L Markley, Haruki Nakamura, Sameer Velankar, Stephen K Burley
OneDep, a unified system for deposition, biocuration, and validation of experimentally determined structures of biological macromolecules to the PDB archive, has been developed as a global collaboration by the worldwide PDB (wwPDB) partners. This new system was designed to ensure that the wwPDB could meet the evolving archiving requirements of the scientific community over the coming decades. OneDep unifies deposition, biocuration, and validation pipelines across all wwPDB, EMDB, and BMRB deposition sites with improved focus on data quality and completeness in these archives, while supporting growth in the number of depositions and increases in their average size and complexity...
March 7, 2017: Structure
Joe G Greener, Ioannis Filippis, Michael J E Sternberg
The related concepts of protein dynamics, conformational ensembles and allostery are often difficult to study with molecular dynamics (MD) due to the timescales involved. We present ExProSE (Exploration of Protein Structural Ensembles), a distance geometry-based method that generates an ensemble of protein structures from two input structures. ExProSE provides a unified framework for the exploration of protein structure and dynamics in a fast and accessible way. Using a dataset of apo/holo pairs it is shown that existing coarse-grained methods often cannot span large conformational changes...
March 7, 2017: Structure
Paula Upla, Seung Joong Kim, Parthasarathy Sampathkumar, Kaushik Dutta, Sean M Cahill, Ilan E Chemmama, Rosemary Williams, Jeffrey B Bonanno, William J Rice, David L Stokes, David Cowburn, Steven C Almo, Andrej Sali, Michael P Rout, Javier Fernandez-Martinez
The membrane ring that equatorially circumscribes the nuclear pore complex (NPC) in the perinuclear lumen of the nuclear envelope is composed largely of Pom152 in yeast and its ortholog Nup210 (or Gp210) in vertebrates. Here, we have used a combination of negative-stain electron microscopy, nuclear magnetic resonance, and small-angle X-ray scattering methods to determine an integrative structure of the ∼120 kDa luminal domain of Pom152. Our structural analysis reveals that the luminal domain is formed by a flexible string-of-pearls arrangement of nine repetitive cadherin-like Ig-like domains, indicating an evolutionary connection between NPCs and the cell adhesion machinery...
March 7, 2017: Structure
Alexandra C Chadwick, Davin R Jensen, Paul J Hanson, Philip T Lange, Sarah C Proudfoot, Francis C Peterson, Brian F Volkman, Daisy Sahoo
The interaction of high-density lipoprotein (HDL) with its receptor, scavenger receptor BI (SR-BI), is critical for lowering plasma cholesterol levels and reducing the risk for cardiovascular disease. The HDL/SR-BI complex facilitates delivery of cholesterol into cells and is likely mediated by receptor dimerization. This work describes the use of nuclear magnetic resonance (NMR) spectroscopy to generate the first high-resolution structure of the C-terminal transmembrane domain of SR-BI. This region of SR-BI harbors a leucine zipper dimerization motif, which when mutated impairs the ability of the receptor to bind HDL and mediate cholesterol delivery...
March 7, 2017: Structure
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