ALBERT

Description: The dysregulated tyrosine kinase BCR-ABL causes chronic myelogenous leukemia in humans and forms a large multiprotein complex that includes the Src-homology 2 (SH2) domain-containing phosphatase 2 (SHP2). The expression of SHP2 is necessary for BCR-ABL-dependent oncogenic transformation, but the precise signaling mechanisms of SHP2 are not well understood. We have...

Description: A number of astronomical systems have been discovered that generate collimated flows of plasma with velocities close to the speed of light. In all cases, the central object is probably a neutron star or black hole and is either accreting material from other stars or is in the initial violent stages of formation. Supercomputer simulations of the production of relativistic jets have been based on a magnetohydrodynamic model, in which differential rotation in the system creates a magnetic coil that simultaneously expels and pinches some of the infalling material. The model may explain the basic features of observed jets, including their speed and amount of collimation, and some of the details in the behavior and statistics of different jet-producing sources.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meier, D L -- Koide, S -- Uchida, Y -- New York, N.Y. -- Science. 2001 Jan 5;291(5501):84-92.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jet Propulsion Laboratory, California Institute of Technology, Pasadena, CA 91109, USA. David.L.Meier@jpl.nasa.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11141552" target="_blank"〉PubMed〈/a〉

Description: Using numerical simulations, we modeled the general relativistic magnetohydrodynamic behavior of a plasma flowing into a rapidly rotating black hole in a large-scale magnetic field. The results show that a torsional Alfven wave is generated by the rotational dragging of space near the black hole. The wave transports energy along the magnetic field lines outward, causing the total energy of the plasma near the hole to decrease to negative values. When this negative energy plasma enters the horizon, the rotational energy of the black hole decreases. Through this process, the energy of the spinning black hole is extracted magnetically〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koide, Shinji -- Shibata, Kazunari -- Kudoh, Takahiro -- Meier, David L -- New York, N.Y. -- Science. 2002 Mar 1;295(5560):1688-91. Epub 2002 Jan 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Faculty of Engineering, Toyama University, Toyama 930-8555, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11809939" target="_blank"〉PubMed〈/a〉

Description: To contend with hazards posed by environmental fluoride, microorganisms export this anion through F(-)-specific ion channels of the Fluc family. Since the recent discovery of Fluc channels, numerous idiosyncratic features of these proteins have been unearthed, including strong selectivity for F(-) over Cl(-) and dual-topology dimeric assembly. To understand the chemical basis for F(-) permeation and how the antiparallel subunits convene to form a F(-)-selective pore, here we solve the crystal structures of two bacterial Fluc homologues in complex with three different monobody inhibitors, with and without F(-) present, to a maximum resolution of 2.1 A. The structures reveal a surprising 'double-barrelled' channel architecture in which two F(-) ion pathways span the membrane, and the dual-topology arrangement includes a centrally coordinated cation, most likely Na(+). F(-) selectivity is proposed to arise from the very narrow pores and an unusual anion coordination that exploits the quadrupolar edges of conserved phenylalanine rings.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stockbridge, Randy B -- Kolmakova-Partensky, Ludmila -- Shane, Tania -- Koide, Akiko -- Koide, Shohei -- Miller, Christopher -- Newstead, Simon -- 102890/Z/13/Z/Wellcome Trust/United Kingdom -- K99 GM111767/GM/NIGMS NIH HHS/ -- K99-GM-111767/GM/NIGMS NIH HHS/ -- R01 GM107023/GM/NIGMS NIH HHS/ -- R01-GM107023/GM/NIGMS NIH HHS/ -- U54 GM087519/GM/NIGMS NIH HHS/ -- U54-GM087519/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 24;525(7570):548-51. doi: 10.1038/nature14981. Epub 2015 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Howard Hughes Medical Institute, Brandeis University, Waltham, Massachusetts 02454, USA. ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA. ; Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford OX1 3QU, UK. ; Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26344196" target="_blank"〉PubMed〈/a〉

Description: The functions of G-protein-coupled receptors (GPCRs) are primarily mediated and modulated by three families of proteins: the heterotrimeric G proteins, the G-protein-coupled receptor kinases (GRKs) and the arrestins. G proteins mediate activation of second-messenger-generating enzymes and other effectors, GRKs phosphorylate activated receptors, and arrestins subsequently bind phosphorylated receptors and cause receptor desensitization. Arrestins activated by interaction with phosphorylated receptors can also mediate G-protein-independent signalling by serving as adaptors to link receptors to numerous signalling pathways. Despite their central role in regulation and signalling of GPCRs, a structural understanding of beta-arrestin activation and interaction with GPCRs is still lacking. Here we report the crystal structure of beta-arrestin-1 (also called arrestin-2) in complex with a fully phosphorylated 29-amino-acid carboxy-terminal peptide derived from the human V2 vasopressin receptor (V2Rpp). This peptide has previously been shown to functionally and conformationally activate beta-arrestin-1 (ref. 5). To capture this active conformation, we used a conformationally selective synthetic antibody fragment (Fab30) that recognizes the phosphopeptide-activated state of beta-arrestin-1. The structure of the beta-arrestin-1-V2Rpp-Fab30 complex shows marked conformational differences in beta-arrestin-1 compared to its inactive conformation. These include rotation of the amino- and carboxy-terminal domains relative to each other, and a major reorientation of the 'lariat loop' implicated in maintaining the inactive state of beta-arrestin-1. These results reveal, at high resolution, a receptor-interacting interface on beta-arrestin, and they indicate a potentially general molecular mechanism for activation of these multifunctional signalling and regulatory proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654799/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654799/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shukla, Arun K -- Manglik, Aashish -- Kruse, Andrew C -- Xiao, Kunhong -- Reis, Rosana I -- Tseng, Wei-Chou -- Staus, Dean P -- Hilger, Daniel -- Uysal, Serdar -- Huang, Li-Yin -- Paduch, Marcin -- Tripathi-Shukla, Prachi -- Koide, Akiko -- Koide, Shohei -- Weis, William I -- Kossiakoff, Anthony A -- Kobilka, Brian K -- Lefkowitz, Robert J -- GM072688/GM/NIGMS NIH HHS/ -- GM087519/GM/NIGMS NIH HHS/ -- HL 075443/HL/NHLBI NIH HHS/ -- HL16037/HL/NHLBI NIH HHS/ -- HL70631/HL/NHLBI NIH HHS/ -- NS028471/NS/NINDS NIH HHS/ -- P41 RR011823/RR/NCRR NIH HHS/ -- R01 HL016037/HL/NHLBI NIH HHS/ -- R01 HL070631/HL/NHLBI NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- U01 GM094588/GM/NIGMS NIH HHS/ -- U54 GM074946/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 May 2;497(7447):137-41. doi: 10.1038/nature12120. Epub 2013 Apr 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23604254" target="_blank"〉PubMed〈/a〉

Description: G-protein-coupled receptors (GPCRs) are critically regulated by beta-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the beta2 adrenergic receptor (beta2AR)-G-protein complex, has provided novel insights into the structural basis of receptor activation. However, complementary information has been lacking on the recruitment of beta-arrestins to activated GPCRs, primarily owing to challenges in obtaining stable receptor-beta-arrestin complexes for structural studies. Here we devised a strategy for forming and purifying a functional human beta2AR-beta-arrestin-1 complex that allowed us to visualize its architecture by single-particle negative-stain electron microscopy and to characterize the interactions between beta2AR and beta-arrestin 1 using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and chemical crosslinking. Electron microscopy two-dimensional averages and three-dimensional reconstructions reveal bimodal binding of beta-arrestin 1 to the beta2AR, involving two separate sets of interactions, one with the phosphorylated carboxy terminus of the receptor and the other with its seven-transmembrane core. Areas of reduced HDX together with identification of crosslinked residues suggest engagement of the finger loop of beta-arrestin 1 with the seven-transmembrane core of the receptor. In contrast, focal areas of raised HDX levels indicate regions of increased dynamics in both the N and C domains of beta-arrestin 1 when coupled to the beta2AR. A molecular model of the beta2AR-beta-arrestin signalling complex was made by docking activated beta-arrestin 1 and beta2AR crystal structures into the electron microscopy map densities with constraints provided by HDX-MS and crosslinking, allowing us to obtain valuable insights into the overall architecture of a receptor-arrestin complex. The dynamic and structural information presented here provides a framework for better understanding the basis of GPCR regulation by arrestins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134437/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shukla, Arun K -- Westfield, Gerwin H -- Xiao, Kunhong -- Reis, Rosana I -- Huang, Li-Yin -- Tripathi-Shukla, Prachi -- Qian, Jiang -- Li, Sheng -- Blanc, Adi -- Oleskie, Austin N -- Dosey, Anne M -- Su, Min -- Liang, Cui-Rong -- Gu, Ling-Ling -- Shan, Jin-Ming -- Chen, Xin -- Hanna, Rachel -- Choi, Minjung -- Yao, Xiao Jie -- Klink, Bjoern U -- Kahsai, Alem W -- Sidhu, Sachdev S -- Koide, Shohei -- Penczek, Pawel A -- Kossiakoff, Anthony A -- Woods, Virgil L Jr -- Kobilka, Brian K -- Skiniotis, Georgios -- Lefkowitz, Robert J -- DK090165/DK/NIDDK NIH HHS/ -- GM072688/GM/NIGMS NIH HHS/ -- GM087519/GM/NIGMS NIH HHS/ -- GM60635/GM/NIGMS NIH HHS/ -- HL075443/HL/NHLBI NIH HHS/ -- HL16037/HL/NHLBI NIH HHS/ -- HL70631/HL/NHLBI NIH HHS/ -- MOP-93725/Canadian Institutes of Health Research/Canada -- NS028471/NS/NINDS NIH HHS/ -- R01 DK090165/DK/NIDDK NIH HHS/ -- R01 GM060635/GM/NIGMS NIH HHS/ -- R01 GM072688/GM/NIGMS NIH HHS/ -- R01 HL016037/HL/NHLBI NIH HHS/ -- R01 HL070631/HL/NHLBI NIH HHS/ -- R01 NS028471/NS/NINDS NIH HHS/ -- UL1 TR000430/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Aug 14;512(7513):218-22. doi: 10.1038/nature13430. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur 208016, India. [3]. ; 1] Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2]. ; 1] Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2]. ; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Chemistry, University of California at San Diego, La Jolla, California 92093, USA. ; Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; School of Pharmaceutical &Life Sciences, Changzhou University, Changzhou, Jiangsu 213164, China. ; Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada. ; Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637, USA. ; Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77054, USA. ; 1] Department of Chemistry, University of California at San Diego, La Jolla, California 92093, USA [2]. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 279 Campus Drive, Stanford, California 94305, USA. ; 1] Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Biochemistry, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043026" target="_blank"〉PubMed〈/a〉

Description: The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. We present the reconstitution and interdisciplinary analyses of the ~425-kilodalton inner ring complex (IRC), which forms the central transport channel and diffusion barrier of the NPC, revealing its interaction network and equimolar stoichiometry. The Nsp1*Nup49*Nup57 channel nucleoporin heterotrimer (CNT) attaches to the IRC solely through the adaptor nucleoporin Nic96. The CNT*Nic96 structure reveals that Nic96 functions as an assembly sensor that recognizes the three-dimensional architecture of the CNT, thereby mediating the incorporation of a defined CNT state into the NPC. We propose that the IRC adopts a relatively rigid scaffold that recruits the CNT to primarily form the diffusion barrier of the NPC, rather than enabling channel dilation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stuwe, Tobias -- Bley, Christopher J -- Thierbach, Karsten -- Petrovic, Stefan -- Schilbach, Sandra -- Mayo, Daniel J -- Perriches, Thibaud -- Rundlet, Emily J -- Jeon, Young E -- Collins, Leslie N -- Huber, Ferdinand M -- Lin, Daniel H -- Paduch, Marcin -- Koide, Akiko -- Lu, Vincent -- Fischer, Jessica -- Hurt, Ed -- Koide, Shohei -- Kossiakoff, Anthony A -- Hoelz, Andre -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- P30-CA014599/CA/NCI NIH HHS/ -- R01-GM090324/GM/NIGMS NIH HHS/ -- R01-GM111461/GM/NIGMS NIH HHS/ -- U01-GM094588/GM/NIGMS NIH HHS/ -- U54-GM087519/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 2;350(6256):56-64. doi: 10.1126/science.aac9176. Epub 2015 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, CA 91125, USA. ; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. ; Biochemistry Center of Heidelberg University, 69120 Heidelberg, Germany. ; California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, CA 91125, USA. hoelz@caltech.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26316600" target="_blank"〉PubMed〈/a〉