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Ian Mitchelle S de Vera, Paola Munoz-Tello, Jie Zheng, Venkatasubramanian Dharmarajan, David P Marciano, Edna Matta-Camacho, Pankaj Kumar Giri, Jinsai Shang, Travis S Hughes, Mark Rance, Patrick R Griffin, Douglas J Kojetin
Nuclear receptor-related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution nuclear magnetic resonance spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurr1 LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids...
October 25, 2018: Structure
Kalli Kappel, Rhiju Das
RNA-protein complexes underlie numerous cellular processes including translation, splicing, and posttranscriptional regulation of gene expression. The structures of these complexes are crucial to their functions but often elude high-resolution structure determination. Computational methods are needed that can integrate low-resolution data for RNA-protein complexes while modeling de novo the large conformational changes of RNA components upon complex formation. To address this challenge, we describe RNP-denovo, a Rosetta method to simultaneously fold-and-dock RNA to a protein surface...
October 25, 2018: Structure
Eduard Baquero, Juliette Fedry, Pierre Legrand, Thomas Krey, Felix A Rey
The cellular fusion protein HAP2, which is structurally homologous to viral class II fusion proteins, drives gamete fusion across several eukaryotic kingdoms. Gamete fusion is a highly controlled process in eukaryotes, and is allowed only between same species gametes. In spite of a conserved architecture, HAP2 displays several species-specific functional regions that were not resolved in the available X-ray structure of the green alga Chlamydomonas reinhardtii HAP2 ectodomain. Here we present an X-ray structure resolving these regions, showing a target membrane interaction surface made by three amphipathic helices in a horseshoe-shaped arrangement...
October 19, 2018: Structure
Robert Yan, Havva Yalinca, Francesca Paoletti, Francesco Gobbo, Laura Marchetti, Antonija Kuzmanic, Doriano Lamba, Francesco Luigi Gervasio, Petr V Konarev, Antonino Cattaneo, Annalisa Pastore
Nerve growth factor (NGF) is an important neurotrophic factor involved in the regulation of cell differentiation and survival of target neurons. Expressed as a proNGF precursor, NGF is matured by furin-mediated protease cleavage. Increasing evidence suggests that NGF and proNGF have distinct functional roles. While the structure of mature NGF is available, little is known about that of the pro-domain because of its dynamical structural features. We exploited an ad hoc hybrid strategy based on nuclear magnetic resonance and modeling validated by small-angle X-ray scattering to gain novel insights on the pro-domain, both in isolation and in the context of proNGF...
October 19, 2018: Structure
Brandon Frenz, Sebastian Rämisch, Andrew J Borst, Alexandra C Walls, Jared Adolf-Bryfogle, William R Schief, David Veesler, Frank DiMaio
Recent advances in single-particle cryo-electron microscopy (cryoEM) have resulted in determination of an increasing number of protein structures with resolved glycans. However, existing protocols for the refinement of glycoproteins at low resolution have failed to keep up with these advances. As a result, numerous deposited structures contain glycan stereochemical errors. Here, we describe a Rosetta-based approach for both cryoEM and X-ray crystallography refinement of glycoproteins that is capable of correcting conformational and configurational errors in carbohydrates...
October 18, 2018: Structure
Massimiliano Bonomi, Samuel Hanot, Charles H Greenberg, Andrej Sali, Michael Nilges, Michele Vendruscolo, Riccardo Pellarin
Cryo-electron microscopy (cryo-EM) has become a mainstream technique for determining the structures of complex biological systems. However, accurate integrative structural modeling has been hampered by the challenges in objectively weighing cryo-EM data against other sources of information due to the presence of random and systematic errors, as well as correlations, in the data. To address these challenges, we introduce a Bayesian scoring function that efficiently and accurately ranks alternative structural models of a macromolecular system based on their consistency with a cryo-EM density map as well as other experimental and prior information...
October 12, 2018: Structure
Philippe Youkharibache, Stella Veretnik, Qingliang Li, Kimberly A Stanek, Cameron Mura, Philip E Bourne
The small β-barrel (SBB) is an ancient protein structural domain characterized by extremes: it features a broad range of structural varieties, a deeply intricate evolutionary history, and it is associated with a bewildering array of cellular pathways. Here, we present a thorough, survey-based analysis of the structural properties of SBBs. We first consider the defining properties of the SBB, including various systems of nomenclature used to describe it, and we introduce the unifying concept of an "urfold...
October 12, 2018: Structure
Tatu J K Haataja, Rafael C Bernardi, Simon Lecointe, Romain Capoulade, Jean Merot, Ulla Pentikäinen
Filamin A (FLNa), expressed in endocardial endothelia during fetal valve morphogenesis, is key in cardiac development. Missense mutations in FLNa cause non-syndromic mitral valve dysplasia (FLNA-MVD). Here, we aimed to reveal the currently unknown underlying molecular mechanism behind FLNA-MVD caused by the FLNa P637Q mutation. The solved crystal structure of the FLNa3-5 P637Q revealed that this mutation causes only minor structural changes close to mutation site. These changes were observed to significantly affect FLNa's ability to transmit cellular force and to interact with its binding partner...
October 9, 2018: Structure
Takaharu Mori, Marta Kulik, Osamu Miyashita, Jaewoon Jung, Florence Tama, Yuji Sugita
Flexible fitting is a powerful technique to build the 3D structures of biomolecules from cryoelectron microscopy (cryo-EM) density maps. One popular method is a cross-correlation coefficient-based approach, where the molecular dynamics (MD) simulation is carried out with the biasing potential that includes the cross-correlation coefficient between the experimental and simulated density maps. Here, we propose efficient parallelization schemes for the calculation of the cross-correlation coefficient to accelerate flexible fitting...
October 4, 2018: Structure
Takamitsu Haruyama, Yasunori Sugano, Noriyuki Kodera, Takayuki Uchihashi, Toshio Ando, Yoshiki Tanaka, Hiroki Konno, Tomoya Tsukazaki
Membrane proteins play important roles in various cellular functions. To analyze membrane proteins, nanodisc technology using membrane scaffold proteins allows single membrane protein units to be embedded into the lipid bilayer disc without detergents. Recent advancements in high-speed atomic force microscopy (HS-AFM) have enabled us to monitor the real-time dynamics of proteins in solution at the nanometer scale. In this study, we report HS-AFM imaging of membrane proteins reconstituted into nanodiscs using two membrane protein complexes, SecYEG complex and MgtE dimer...
October 4, 2018: Structure
Wei Wang, Xinguo Chen, Sandra L Wolin, Yong Xiong
Noncoding Y RNAs are present in both animal cells and many bacteria. In all species examined, Y RNAs tether the Ro60 protein to an effector protein to perform various cellular functions. Recently, a new Y RNA subfamily was identified in bacteria. Bioinformatic analyses of these YrlA (Y RNA-like A) RNAs predict that the effector-binding domain resembles tRNA. We present the structure of this domain, the overall folding of which is strikingly similar to canonical tRNAs. The tertiary interactions that are responsible for stabilizing tRNA are present in YrlA, making it a close tRNA mimic...
September 27, 2018: Structure
Kai-En Chen, Vikas A Tillu, Mintu Chandra, Brett M Collins
Phosphorylation of phosphoinositides by the class II phosphatidylinositol 3-kinase (PI3K) PI3K-C2α is essential for many processes, including neuroexocytosis and formation of clathrin-coated vesicles. A defining feature of the class II PI3Ks is a C-terminal module composed of phox-homology (PX) and C2 membrane interacting domains; however, the mechanisms that control their specific cellular localization remain poorly understood. Here we report the crystal structure of the C2 domain of PI3K-C2α in complex with the phosphoinositide head-group mimic inositol hexaphosphate, revealing two distinct pockets for membrane binding...
September 19, 2018: Structure
Heng Zhang, Xueyong Zhu, Gabriel Pascual, Jehangir S Wadia, Elissa Keogh, Jeroen J Hoozemans, Berdien Siregar, Hanna Inganäs, Esther J M Stoop, Jaap Goudsmit, Adrian Apetri, Wouter Koudstaal, Ian A Wilson
Aggregation of the hyperphosphorylated protein tau into neurofibrillary tangles and neuropil threads is a hallmark of Alzheimer disease (AD). Identification and characterization of the epitopes recognized by anti-tau antibodies might shed light on the molecular mechanisms of AD pathogenesis. Here we report on the biochemical and structural characterization of a tau-specific monoclonal antibody CBTAU-24.1, which was isolated from the human memory B cell repertoire. Immunohistochemical staining with CBTAU-24...
September 12, 2018: Structure
John Faissal Haddad, Yidai Yang, Yoh-Hei Takahashi, Monika Joshi, Nidhi Chaudhary, Ashley Woodfin, Aissa Benyoucef, Sylvain Yeung, Joseph S Brunzelle, Georgios Skiniotis, Marjorie Brand, Ali Shilatifard, Jean-François Couture
Dpy-30 is a regulatory subunit controlling the histone methyltransferase activity of the KMT2 enzymes in vivo. Paradoxically, in vitro methyltransferase assays revealed that Dpy-30 only modestly participates in the positive heterotypic allosteric regulation of these methyltransferases. Detailed genome-wide, molecular and structural studies reveal that an extensive network of interactions taking place at the interface between Dpy-30 and Ash2L are critical for the correct placement, genome-wide, of H3K4me2 and H3K4me3 but marginally contribute to the methyltransferase activity of KMT2 enzymes in vitro...
September 10, 2018: Structure
Yonathan Goldtzvik, Mauro Lorenzo Mugnai, D Thirumalai
Cytoplasmic dynein, whose motor domain belongs to the AAA+ family, walks on microtubules toward the minus end. Using the available structures in different nucleotide states, we performed simulations of a coarse-grained model to elucidate the dynamics of allosteric transitions. Binding of ATP closes the cleft between the AAA1 and AAA2 domains, triggering conformational changes in the rest of the motor domain, thus forming the pre-power stroke state. Interactions with the microtubule, modeled implicitly, enhance ADP release rate, and the formation of the post-power stroke state...
August 28, 2018: Structure
Kelly R Karch, Mariel Coradin, Levani Zandarashvili, Zhong-Yuan Kan, Morgan Gerace, S Walter Englander, Ben E Black, Benjamin A Garcia
Until recently, a major limitation of hydrogen-deuterium exchange mass spectrometry (HDX-MS) was that resolution of deuterium localization was limited to the length of the peptide generated during proteolysis. However, electron transfer dissociation (ETD) has been shown to preserve deuterium label in the gas phase, enabling better resolution. To date, this technology remains mostly limited to small, already well-characterized proteins. Here, we optimize, expand, and adapt HDX-MS tandem MS (MS/MS) capabilities to accommodate histone and nucleosomal complexes on top-down HDX-MS/MS and middle-down HDX-MS/MS platforms and demonstrate that near site-specific resolution of deuterium localization can be obtained with high reproducibility...
August 25, 2018: Structure
Cristina Risi, Betty Belknap, Eva Forgacs-Lonart, Samantha P Harris, Gunnar F Schröder, Howard D White, Vitold E Galkin
Muscle contraction relies on interaction between myosin-based thick filaments and actin-based thin filaments. Myosin binding protein C (MyBP-C) is a key regulator of actomyosin interactions. Recent studies established that the N'-terminal domains (NTDs) of MyBP-C can either activate or inhibit thin filaments, but the mechanism of their collective action is poorly understood. Cardiac MyBP-C (cMyBP-C) harbors an extra NTD, which is absent in skeletal isoforms of MyBP-C, and its role in regulation of cardiac contraction is unknown...
August 25, 2018: Structure
Franziska Preuß, Sebastian Mathea, Stefan Knapp
No abstract text is available yet for this article.
November 6, 2018: Structure
Céline Lecointre, Valérie Simon, Clément Kerneur, Frédéric Allemand, Aurélie Fournet, Ingrid Montarras, Jean-Luc Pons, Muriel Gelin, Constance Brignatz, Serge Urbach, Gilles Labesse, Serge Roche
No abstract text is available yet for this article.
November 6, 2018: Structure
Anthony E Pegg
A critical function of spermidine is in the formation of hypusine, an essential post-translational modification of eukaryotic initiation factor eIF5A. In this issue of Structure, Afandor et al. (2018) determine the crystal structure of trypanosomal deoxyhypusine synthase, which shows that gene duplication and subsequent mutations provide significant differences from the mammalian equivalent exploitable for drug design.
November 6, 2018: Structure
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