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Nature Structural & Molecular Biology

Navid Paknejad, Richard K Hite
Inositol trisphosphate receptors (IP3 Rs) are ubiquitous Ca2+ -permeable channels that mediate release of Ca2+ from the endoplasmic reticulum, thereby regulating numerous processes including cell division, cell death, differentiation and fertilization. IP3 Rs are jointly activated by inositol trisphosphate (IP3 ) and their permeant ion, Ca2+ . At high concentrations, however, Ca2+ inhibits activity, ensuring precise spatiotemporal control over intracellular Ca2+ . Despite extensive characterization of IP3 R, the mechanisms through which these molecules control channel gating have remained elusive...
July 16, 2018: Nature Structural & Molecular Biology
Sylvain Daujat, Thomas Weiss, Fabio Mohn, Ulrike C Lange, Céline Ziegler-Birling, Ulrike Zeissler, Michael Lappe, Dirk Schübeler, Maria-Elena Torres-Padilla, Robert Schneider
In this article, the Ponceau staining presented in Fig. 1b (right, bottom) does not follow best practices for figure preparation since itinadvertently included duplications from the Ponceau staining presented in Supplementary Fig. 1b (for which the same preparation ofnucleosomes from HeLa cells had been used). A new Fig. 1b is provided in the Author Correction.
July 11, 2018: Nature Structural & Molecular Biology
Lucas Kuhlen, Patrizia Abrusci, Steven Johnson, Joseph Gault, Justin Deme, Joseph Caesar, Tobias Dietsche, Mehari Tesfazgi Mebrhatu, Tariq Ganief, Boris Macek, Samuel Wagner, Carol V Robinson, Susan M Lea
Export of proteins through type III secretion systems is critical for motility and virulence of many major bacterial pathogens. Three putative integral membrane proteins (FliP, FliQ, FliR) are suggested to form the core of an export gate in the inner membrane, but their structure, assembly and location within the final nanomachine remain unclear. Here, we present the cryoelectron microscopy structure of the Salmonella Typhimurium FliP-FliQ-FliR complex at 4.2 Å. None of the subunits adopt canonical integral membrane protein topologies, and common helix-turn-helix structural elements allow them to form a helical assembly with 5:4:1 stoichiometry...
July 2, 2018: Nature Structural & Molecular Biology
Véronique Sauvé, George Sung, Naoto Soya, Guennadi Kozlov, Nina Blaimschein, Lis Schwartz Miotto, Jean-François Trempe, Gergely L Lukacs, Kalle Gehring
Mutations in the ubiquitin ligase parkin are responsible for a familial form of Parkinson's disease. Parkin and the PINK1 kinase regulate a quality-control system for mitochondria. PINK1 phosphorylates ubiquitin on the outer membrane of damaged mitochondria, thus leading to recruitment and activation of parkin via phosphorylation of its ubiquitin-like (Ubl) domain. Here, we describe the mechanism of parkin activation by phosphorylation. The crystal structure of phosphorylated Bactrocera dorsalis (oriental fruit fly) parkin in complex with phosphorylated ubiquitin and an E2 ubiquitin-conjugating enzyme reveals that the key activating step is movement of the Ubl domain and release of the catalytic RING2 domain...
July 2, 2018: Nature Structural & Molecular Biology
Szymon W Manka, Carolyn A Moores
Microtubules form from longitudinally and laterally assembling tubulin α-β dimers. The assembly induces strain in tubulin, resulting in cycles of microtubule catastrophe and regrowth. This 'dynamic instability' is governed by GTP hydrolysis that renders the microtubule lattice unstable, but it is unclear how. We used a human microtubule nucleating and stabilizing neuronal protein, doublecortin, and high-resolution cryo-EM to capture tubulin's elusive hydrolysis intermediate GDP•Pi state, alongside the prehydrolysis analog GMPCPP state and the posthydrolysis GDP state with and without an anticancer drug, Taxol...
July 2, 2018: Nature Structural & Molecular Biology
Vyacheslav Akimov, Inigo Barrio-Hernandez, Sten V F Hansen, Philip Hallenborg, Anna-Kathrine Pedersen, Dorte B Bekker-Jensen, Michele Puglia, Stine D K Christensen, Jens T Vanselow, Mogens M Nielsen, Irina Kratchmarova, Christian D Kelstrup, Jesper V Olsen, Blagoy Blagoev
Ubiquitination is a post-translational modification (PTM) that is essential for balancing numerous physiological processes. To enable delineation of protein ubiquitination at a site-specific level, we generated an antibody, denoted UbiSite, recognizing the C-terminal 13 amino acids of ubiquitin, which remain attached to modified peptides after proteolytic digestion with the endoproteinase LysC. Notably, UbiSite is specific to ubiquitin. Furthermore, besides ubiquitination on lysine residues, protein N-terminal ubiquitination is readily detected as well...
July 2, 2018: Nature Structural & Molecular Biology
Nicholas O Bodnar, Kelly H Kim, Zhejian Ji, Thomas E Wales, Vladimir Svetlov, Evgeny Nudler, John R Engen, Thomas Walz, Tom A Rapoport
Many polyubiquitinated proteins are extracted from membranes or complexes by the conserved ATPase Cdc48 (in yeast; p97 or VCP in mammals) before proteasomal degradation. Each Cdc48 hexamer contains two stacked ATPase rings (D1 and D2) and six N-terminal (N) domains. Cdc48 binds various cofactors, including the Ufd1-Npl4 heterodimer. Here, we report structures of the Cdc48-Ufd1-Npl4 complex from Chaetomium thermophilum. Npl4 interacts through its UBX-like domain with a Cdc48 N domain, and it uses two Zn2+ -finger domains to anchor the enzymatically inactive Mpr1-Pad1 N-terminal (MPN) domain, homologous to domains found in several isopeptidases, to the top of the D1 ATPase ring...
July 2, 2018: Nature Structural & Molecular Biology
Maria Victoria Botuyan, Gaofeng Cui, Pascal Drané, Catarina Oliveira, Alexandre Detappe, Marie Eve Brault, Nishita Parnandi, Shweta Chaubey, James R Thompson, Benoît Bragantini, Debiao Zhao, J Ross Chapman, Dipanjan Chowdhury, Georges Mer
Dynamic protein interaction networks such as DNA double-strand break (DSB) signaling are modulated by post-translational modifications. The DNA repair factor 53BP1 is a rare example of a protein whose post-translational modification-binding function can be switched on and off. 53BP1 is recruited to DSBs by recognizing histone lysine methylation within chromatin, an activity directly inhibited by the 53BP1-binding protein TIRR. X-ray crystal structures of TIRR and a designer protein bound to 53BP1 now reveal a unique regulatory mechanism in which an intricate binding area centered on an essential TIRR arginine residue blocks the methylated-chromatin-binding surface of 53BP1...
July 2, 2018: Nature Structural & Molecular Biology
Robert Tunney, Nicholas J McGlincy, Monica E Graham, Nicki Naddaf, Lior Pachter, Liana F Lareau
Synonymous codon choice can have dramatic effects on ribosome speed and protein expression. Ribosome profiling experiments have underscored that ribosomes do not move uniformly along mRNAs. Here, we have modeled this variation in translation elongation by using a feed-forward neural network to predict the ribosome density at each codon as a function of its sequence neighborhood. Our approach revealed sequence features affecting translation elongation and characterized large technical biases in ribosome profiling...
July 2, 2018: Nature Structural & Molecular Biology
Hidetsugu Asada, Shoichiro Horita, Kunio Hirata, Mitsunori Shiroishi, Yuki Shiimura, Hiroko Iwanari, Takao Hamakubo, Tatsuro Shimamura, Norimichi Nomura, Osamu Kusano-Arai, Tomoko Uemura, Chiyo Suno, Takuya Kobayashi, So Iwata
Angiotensin II (AngII) plays a central role in regulating human blood pressure, which is mainly mediated by interactions between AngII and the G-protein-coupled receptors (GPCRs) AngII type 1 receptor (AT1 R) and AngII type 2 receptor (AT2 R). We have solved the crystal structure of human AT2 R binding the peptide ligand [Sar1 , Ile8 ]AngII and its specific antibody at 3.2-Å resolution. [Sar1 , Ile8 ]AngII interacts with both the 'core' binding domain, where the small-molecule ligands of AT1 R and AT2 R bind, and the 'extended' binding domain, which is equivalent to the allosteric modulator binding site of muscarinic acetylcholine receptor...
July 2, 2018: Nature Structural & Molecular Biology
Nicholas B Last, Randy B Stockbridge, Ashley E Wilson, Tania Shane, Ludmila Kolmakova-Partensky, Akiko Koide, Shohei Koide, Christopher Miller
Fluoride/proton antiporters of the CLCF family combat F- toxicity in bacteria by exporting this halide from the cytoplasm. These transporters belong to the widespread CLC superfamily but display transport properties different from those of the well-studied Cl- /H+ antiporters. Here, we report a structural and functional investigation of these F- -transport proteins. Crystal structures of a CLCF homolog from Enterococcus casseliflavus are captured in two conformations with simultaneous accessibility of F- and H+ ions via separate pathways on opposite sides of the membrane...
June 25, 2018: Nature Structural & Molecular Biology
James M Dunce, Orla M Dunne, Matthew Ratcliff, Claudia Millán, Suzanne Madgwick, Isabel Usón, Owen R Davies
Meiotic chromosomes adopt unique structures in which linear arrays of chromatin loops are bound together in homologous chromosome pairs by a supramolecular protein assembly, the synaptonemal complex. This three-dimensional scaffold provides the essential structural framework for genetic exchange by crossing over and subsequent homolog segregation. The core architecture of the synaptonemal complex is provided by SYCP1. Here we report the structure and self-assembly mechanism of human SYCP1 through X-ray crystallographic and biophysical studies...
June 18, 2018: Nature Structural & Molecular Biology
Ahmed-Noor A Agip, James N Blaza, Hannah R Bridges, Carlo Viscomi, Shaun Rawson, Stephen P Muench, Judy Hirst
Complex I (NADH:ubiquinone oxidoreductase) uses the reducing potential of NADH to drive protons across the energy-transducing inner membrane and power oxidative phosphorylation in mammalian mitochondria. Recent cryo-EM analyses have produced near-complete models of all 45 subunits in the bovine, ovine and porcine complexes and have identified two states relevant to complex I in ischemia-reperfusion injury. Here, we describe the 3.3-Å structure of complex I from mouse heart mitochondria, a biomedically relevant model system, in the 'active' state...
June 18, 2018: Nature Structural & Molecular Biology
Matthias W Hentze, Juan Valcárcel
No abstract text is available yet for this article.
June 18, 2018: Nature Structural & Molecular Biology
Rasmus Hansen, Ulf Peters, Anjali Babbar, Yuching Chen, Jun Feng, Matthew R Janes, Lian-Sheng Li, Pingda Ren, Yi Liu, Patrick P Zarrinkar
Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRASG12C inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRASG12C , while the reversible binding affinity is weak, in the hundreds of micromolar or higher range...
May 14, 2018: Nature Structural & Molecular Biology
Alexander V Statsyuk
No abstract text is available yet for this article.
May 14, 2018: Nature Structural & Molecular Biology
Helen Walden, Katrin Rittinger
RBR ligases are an enigmatic class of E3 ubiquitin ligases that combine properties of RING and HECT-type E3s and undergo multilevel regulation through autoinhibition, post-translational modifications, multimerization and interaction with binding partners. Here, we summarize recent progress in RBR structures and function, which has uncovered commonalities in the mechanisms by which different family members transfer ubiquitin through a multistep process. However, these studies have also highlighted clear differences in the activity of different family members, suggesting that each RBR ligase has evolved specific properties to fit the biological process it regulates...
May 7, 2018: Nature Structural & Molecular Biology
Andrija Sente, Raphael Peer, Ashish Srivastava, Mithu Baidya, Arthur M Lesk, Santhanam Balaji, Arun K Shukla, M Madan Babu, Tilman Flock
Arrestins regulate the signaling of ligand-activated, phosphorylated G-protein-coupled receptors (GPCRs). Different patterns of receptor phosphorylation (phosphorylation barcode) can modulate arrestin conformations, resulting in distinct functional outcomes (for example, desensitization, internalization, and downstream signaling). However, the mechanism of arrestin activation and how distinct receptor phosphorylation patterns could induce different conformational changes on arrestin are not fully understood...
June 2018: Nature Structural & Molecular Biology
Hsiang-Ting Lei, Jinming Ma, Silvia Sanchez Martinez, Tamir Gonen
Recent advances in understanding intracellular amino acid transport and mechanistic target of rapamycin complex 1 (mTORC1) signaling shed light on solute carrier 38, family A member 9 (SLC38A9), a lysosomal transporter responsible for the binding and translocation of several essential amino acids. Here we present the first crystal structure of SLC38A9 from Danio rerio in complex with arginine. As captured in the cytosol-open state, the bound arginine was locked in a transitional state stabilized by transmembrane helix 1 (TM1) of drSLC38A9, which was anchored at the groove between TM5 and TM7...
June 2018: Nature Structural & Molecular Biology
Alisa A Garaeva, Gert T Oostergetel, Cornelius Gati, Albert Guskov, Cristina Paulino, Dirk J Slotboom
Human ASCT2 belongs to the SLC1 family of secondary transporters and is specific for the transport of small neutral amino acids. ASCT2 is upregulated in cancer cells and serves as the receptor for many retroviruses; hence, it has importance as a potential drug target. Here we used single-particle cryo-EM to determine a structure of the functional and unmodified human ASCT2 at 3.85-Å resolution. ASCT2 forms a homotrimeric complex in which each subunit contains a transport and a scaffold domain. Prominent extracellular extensions on the scaffold domain form the predicted docking site for retroviruses...
June 2018: Nature Structural & Molecular Biology
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