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Mapping the Cell Symposium: RNA Platform Wednesday, March 6, 2019 451a Symposium: Mapping the Cell by four ankyrin repeats, the linker helical domain (LHD1-9), and the pre-S1 elbow. The N-terminus is followed by six membrane-spanning helices (S1-S6) 2230-Symp and a pore helix connecting to a re-entrant loop that forms the selectivity filter. Simultaneous Cross-Evaluation of Heterogeneous E. coli Datasets via The TRP helix is immediately adjacent to S6, and the C-terminus consists of two Mechanistic Simulation alpha-helices connected by a small linker. TRPC3 transmembrane domain re- Markus Covert. sembles those of other TRP channels, whereas the CPD features major differ- Dept Bioengineering, Stanford Univ, Stanford, CA, USA. ences. A C-terminal domain swap occurs at the center of the CPD, where The extensive heterogeneity of biological data poses challenges to analysis and horizontal helices (HH) transition into a coiled-coil bundle, highlighting a interpretation. Construction of a large-scale mechanistic model of Escherichia unique fold for the TRPC subfamily. Comparison of TRPC3 structures reveals coli enabled us to integrate and cross-evaluate a massive, heterogeneous dataset that the HH can reside in two distinct positions. Electrophysiological analyses based on measurements reported by various labs over decades. We identified in- demonstrate that TRPC3 activity increases by shortening the length of the C-ter- consistencies with functional consequences across the data, including: that the minal loop connecting the HH with the TRP helices; likewise elongating the data describing total output of the ribosomes and RNA polymerases is not suffi- length of the loop has the opposite effect. Our findings demonstrate that the C- cient for a cell to reproduce measured doubling times; that measured metabolic terminal loop impacts channel gating by altering the allosteric coupling between parameters are neither fully compatible with each other nor with overall growth; the cytoplasmic and transmembrane domains. Future functional and structural that essential proteins are absent during the cell cycle - and the cell is robust to experiments are underway to validate whether the upward movement of the this absence. Finally, considering these data as a whole leads to successful pre- HHs corresponds to a positive modulation of the TRPC3 gating cycle. dictions of new experimental outcomes, in this case protein half-lives. 2234-Plat 2231-Symp Structural Insights into Ligand Modulation of the TRPV2 Channel Towards a Model of the Human Pancreatic Beta Cell Ruth Pumroy1, Amrita Samanta2, Yuhang Liu3, Franklin Pozo2, Raymond C. Stevens. Taylor Hughes1, George R. Dubyak2, Seungil Han3, David T. Lodowski2, Bridge Institute, University of Southern California, Los Angeles, CA, USA. Vera Moiseenkova-Bell1. A key scientific challenge in biology and chemistry is the integration of data 1Department of Pharmacology, University of Pennsylvania, Philadelphia, across the different scales – molecular, cellular, and whole body. In a collabo- PA, USA, 2Case Western Reserve University, Cleveland, OH, USA, 3Pfizer rative open source effort with several different groups across California and Inc, Groton, CT, USA. Shanghai, we are workings towards a multi-scale model of the human pancre- The transient receptor potential (TRP) family of ion channels permits permeation atic beta cell at atomic resolution. Such a model will be useful for advancing the of essential ions, including Naþ and Ca2þ, through the plasma membrane. Mem- field of structure based drug design from the protein scale to the cellular scale bers of the Vanilloid subset of this family (TRPV) can be activated or inhibited by and provide us with better feedback in the understanding and design of new a variety of stimuli, including heat, pH, mechanosensation, and a variety of small medicines to treat type II diabetes. We invite all groups interested in this effort molecules. Agonist activation of TRPV2 plays a role in the inhibition of a variety to join called the Pancreatic Beta Cell Consortium https://dornsife.usc.edu/ of cancers, including glioblastoma multiforme cell proliferation. The mechanism bridge-institute/pancreatic-beta-cell-consortium/. of TRPV2 activity in these cases seems to be related to increasing the uptake of some anticancer therapeutics, like temozolomide and doxorubicin. Here we pre- Symposium: RNA sent structures of TRPV2 structures in apo and ligand-bound forms resolved by cryo-electron microscopy. In this work we have found a novel ligand binding 2232-Symp pocket for TRPV2 which could lead to future drug development. Untangling Messenger RNA Structure with Dead-Box RNA Helicases Elizabeth Tran. 2235-Plat Biochemistry, Purdue University, West Lafayette, IN, USA. Multimerization of Human TRPA1 Ion Channel Cytoplasmic Domains DEAD-box proteins constitute the largest RNA helicase family in eukaryotes, Gilbert Q. Martinez, Sharona E. Gordon. functioning in all aspects of gene expression. However, the mechanism of ac- Dept Physiol/Biophys, Univ Washington, Seattle, WA, USA. tion in cells for these helicases remains elusive. Over the last several years, we The transient receptor potential Ankyrin-1 (TRPA1) ion channel is modu- have used genetics and classic biochemical techniques to provide insight into lated by myriad noxious stimuli that interact with multiple regions of the the role of the DEAD-box RNA helicase Dbp2 in S. cerevisiae, revealing con- channel, including the cytoplasmic N-terminal Ankyrin repeat domains nections between RNA duplex unwinding and nuclear messenger RNA matu- (ARDs) via covalent modification. The way in which TRPA1 cytoplasmic ration steps. However, the precise enzymatic targets of Dbp2 and the vast domain modification is transmitted across large spatial distances to open majority of the 25-40 DEAD-box RNA helicases in eukaryotes. Using a com- thechannelporehasyettobeelucidated.Thecryo-EMstructureof bination of genome-wide techniques including iCLIP-seq, Structure-seq, and TRPA1 revealed a tetrameric C-terminal coiled-coil (CC) surrounded by RNA seq, we have now characterized the enzymatic targets of Dbp2. This re- the ARDs, an architecture shared with the canonical transient receptor po- veals a role for dynamic changes in RNA structure during transcriptional termi- tential (TRPC) ion channel family. Similarly, structures of the TRP mela- nation. Moreover, we find evidence for regulation of Dbp2 and, consequently, statin (TRPM) ion channel family also showed a C-terminal coiled-coil Dbp2-dependent mRNAs, in response to glucose availability. These findings enclosed by N-terminal cytoplasmic domains. This conserved architecture correlate with changes in metabolic gene expression and provide support for may indicate a common gating mechanism in which modification of cyto- widespread regulation of RNA structure as a mechanism of gene regulation. plasmic domains can transduce conformational changes to open the ion- conducting pore. We developed an in vitro system in which N-terminal ARDs and C-terminal CC domains can be expressed in bacteria and main- Platform: TRP Channels tain the ability to interact. We tested whether temperature, the polyphos- phate compound IP6, and the covalent modifier allyl isothiocyanate alters 2233-Plat N- and C-terminal interactions. We found that none of the modifications Structural and Functional Analyses of TRPC3 Reveal Allosteric Gating tested altered ARD-CC interactions. We found that CCs tetramerize in a Modulation by the Cytoplasmic Domain concentration dependent manner, with monomers and trimers observed at Francisco J. Sierra Valdez1, Caleigh M. Azumaya2, Luis O. Romero1, lower concentrations. Although we did not observe ligand- or Terunaga Nakagawa2, Julio F. Cordero-Morales1. temperature-dependent disruption of ARD-CC interactions, our system pro- 1Dept Physiology, Univ Tennessee, Memphis, TN, USA, 2Vanderbilt vides a method for examining the mechanism of oligomerization of TRPA1 University, Nashville, TN, USA. cytoplasmic domains. TRPC3 is associated with neurodegenerative diseases, memory loss, and hyper- tension. In blood vessels, TRPC3 is an essential component of the cellular mech- 2236-Plat anisms by which vasoconstrictors regulate blood pressure. Vasoconstrictors, Approaching to the Molecular Mechanism of the Fast Inactivation of such as angiotensin II, bind to phospholipase C (PLC)-coupled receptors, Calcium Selective TRP Channels increasing the intracellular levels of DAG, which in turn activates TRPC3. Lisandra Flores Aldama1, Kattina Zavala2, Daniel Bustos3, Upon activation, TRPC3 channels induce depolarization increases intracellular Wendy Gonzalez3, Juan Opazo2, Sebastian E. Brauchi1. þ Ca2 and promotes vasoconstriction. Here, we show the full-length and cyto- 1Physiology, Univ Austral de Chile, Valdivia, Chile, 2Faculty of Science, plasmic domain (CPD) cryoEM structures for human TRPC3 in the apo state Universidad Austral de Chile, Valdivia, Chile, 3Universidad de Talca, Talca, at 5.8 and 4.0 A˚ resolution. A TRPC3 subunit consists of an N-terminus formed Chile. BPJ 9439_9446 452a Wednesday, March 6, 2019 TRPV5 and TRPV6 are inwardly rectifying calcium selective channels, 2239-Plat considered as gatekeepers of epithelial calcium transport and key elements Gain-Of-Function Mutationsin TRPM4 Activation Gate Cause Skin Dis- for calcium homeostasis. Intracellular calcium exert a negative control over ease PSEK the activity of these channels. In mammals, TRPV6 channels show a charac- Huijun Wang1, Zhe Xu2, Bo Hyun Lee3, Simon Vu3, Linghan Hu1, teristic fast calcium-dependent
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