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Structural basis of the activation of a metabotropic GABA receptor 期刊论文
NATURE, 2020
作者:  Montagne, Axel;  39;Orazio, Lina M.
收藏  |  浏览/下载:8/0  |  提交时间:2020/07/03

Metabotropic gamma-aminobutyric acid receptors (GABA(B)) are involved in the modulation of synaptic responses in the central nervous system and have been implicated in neuropsychological conditions that range from addiction to psychosis(1). GABA(B)belongs to class C of the G-protein-coupled receptors, and its functional entity comprises an obligate heterodimer that is composed of the GB1 and GB2 subunits(2). Each subunit possesses an extracellular Venus flytrap domain, which is connected to a canonical seven-transmembrane domain. Here we present four cryo-electron microscopy structures of the human full-length GB1-GB2 heterodimer: one structure of its inactive apo state, two intermediate agonist-bound forms and an active form in which the heterodimer is bound to an agonist and a positive allosteric modulator. The structures reveal substantial differences, which shed light on the complex motions that underlie the unique activation mechanism of GABA(B). Our results show that agonist binding leads to the closure of the Venus flytrap domain of GB1, triggering a series of transitions, first rearranging and bringing the two transmembrane domains into close contact along transmembrane helix 6 and ultimately inducing conformational rearrangements in the GB2 transmembrane domain via a lever-like mechanism to initiate downstream signalling. This active state is stabilized by a positive allosteric modulator binding at the transmembrane dimerization interface.


Cryo-electron microscopy structures of apo, agonist- and positive allosteric modulator-bound forms of the GB1-GB2 heterodimer of the metabotropic gamma-aminobutyric acid (GABA) receptor shed light on the activation mechanism of this receptor.


  
Hydrogen peroxide sensor HPCA1 is an LRR receptor kinase in Arabidopsis 期刊论文
NATURE, 2020, 578 (7796) : 577-+
作者:  Bogomilov, M.;  Tsenov, R.;  Vankova-Kirilova, G.;  Song, Y. P.;  Tang, J. Y.;  Li, Z. H.;  Bertoni, R.;  Bonesini, M.;  Chignoli, F.;  Mazza, R.;  Palladino, V;  de Bari, A.;  Orestano, D.;  Tortora, L.;  Kuno, Y.;  Sakamoto, H.;  Sato, A.;  Ishimoto, S.;  Chung, M.;  Sung, C. K.;  Filthaut, F.;  Jokovic, D.;  Maletic, D.;  Savic, M.;  Jovancevic, N.;  Nikolov, J.;  Vretenar, M.;  Ramberger, S.;  Asfandiyarov, R.;  Blondel, A.;  Drielsma, F.;  Karadzhov, Y.;  Boyd, S.;  Greis, J. R.;  Lord, T.;  Pidcott, C.;  Taylor, I;  Charnley, G.;  Collomb, N.;  Dumbell, K.;  Gallagher, A.;  Grant, A.;  Griffiths, S.;  Hartnett, T.;  Martlew, B.;  Moss, A.;  Muir, A.;  Mullacrane, I;  Oates, A.;  Owens, P.;  Stokes, G.;  Warburton, P.;  White, C.;  Adams, D.;  Bayliss, V;  Boehm, J.;  Bradshaw, T. W.;  Brown, C.;  Courthold, M.;  Govans, J.;  Hills, M.;  Lagrange, J-B;  Macwaters, C.;  Nichols, A.;  Preece, R.;  Ricciardi, S.;  Rogers, C.;  Stanley, T.;  Tarrant, J.;  Tucker, M.;  Watson, S.;  Wilson, A.;  Bayes, R.;  Nugent, J. C.;  Soler, F. J. P.;  Chatzitheodoridis, G. T.;  Dick, A. J.;  Ronald, K.;  Whyte, C. G.;  Young, A. R.;  Gamet, R.;  Cooke, P.;  Blackmore, V. J.;  Colling, D.;  Dobbs, A.;  Dornan, P.;  Franchini, P.;  Hunt, C.;  Jurj, P. B.;  Kurup, A.;  Long, K.;  Martyniak, J.;  Middleton, S.;  Pasternak, J.;  Uchida, M. A.;  Cobb, J. H.;  Booth, C. N.;  Hodgson, P.;  Langlands, J.;  Overton, E.;  Pec, V;  Smith, P. J.;  Wilbur, S.;  Ellis, M.;  Gardener, R. B. S.;  Kyberd, P.;  Nebrensky, J. J.;  DeMello, A.;  Gourlay, S.;  Lambert, A.;  Li, D.;  Luo, T.;  Prestemon, S.;  Virostek, S.;  Palmer, M.;  Witte, H.;  Adey, D.;  Bross, A. D.;  Bowring, D.;  Liu, A.;  Neuffer, D.;  Popovic, M.;  Rubinov, P.;  Freemire, B.;  Hanlet, P.;  Kaplan, D. M.;  Mohayai, T. A.;  Rajaram, D.;  Snopok, P.;  Torun, Y.;  Cremaldi, L. M.;  Sanders, D. A.;  Summers, D. J.;  Coney, L. R.;  Hanson, G. G.;  Heidt, C.
收藏  |  浏览/下载:40/0  |  提交时间:2020/07/03

Hydrogen peroxide (H2O2) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues(1-4). H2O2 enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for H2O2 also exist on the cell surface remains unknown. In plant cells, H2O2 triggers an influx of Ca2+ ions, which is thought to be involved in H2O2 sensing and signalling. Here, by using forward genetic screens based on Ca2+ imaging, we isolated hydrogen-peroxide-induced Ca(2+)increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by H2O2 via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates H2O2-induced activation of Ca2+ channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular H2O2 is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.


HPCA1, a member of a previously uncharacterized subfamily of leucine-rich-repeat receptor-like kinases, is the hydrogen-peroxide sensor at the plasma membrane in Arabidopsis.