IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-51960-z.html
   My bibliography  Save this article

Neurotransmitter recognition by human vesicular monoamine transporter 2

Author

Listed:
  • Dohyun Im

    (Kyoto University)

  • Mika Jormakka

    (Kyoto University)

  • Narinobu Juge

    (Advanced Science Research Center, Okayama University
    Dentistry and Pharmaceutical Sciences, Okayama University)

  • Jun-ichi Kishikawa

    (Kyoto Institute of Technology
    Osaka University)

  • Takayuki Kato

    (Osaka University)

  • Yukihiko Sugita

    (Kyoto University
    Kyoto University
    Kyoto University)

  • Takeshi Noda

    (Kyoto University
    Kyoto University
    Japan Science and Technology Agency)

  • Tomoko Uemura

    (Kyoto University)

  • Yuki Shiimura

    (Kyoto University
    Kurume University)

  • Takaaki Miyaji

    (Advanced Science Research Center, Okayama University
    Dentistry and Pharmaceutical Sciences, Okayama University)

  • Hidetsugu Asada

    (Kyoto University)

  • So Iwata

    (Kyoto University
    RIKEN SPring-8 Center)

Abstract

Human vesicular monoamine transporter 2 (VMAT2), a member of the SLC18 family, plays a crucial role in regulating neurotransmitters in the brain by facilitating their uptake and storage within vesicles, preparing them for exocytotic release. Because of its central role in neurotransmitter signalling and neuroprotection, VMAT2 is a target for neurodegenerative diseases and movement disorders, with its inhibitor being used as therapeutics. Despite the importance of VMAT2 in pharmacophysiology, the molecular basis of VMAT2-mediated neurotransmitter transport and its inhibition remains unclear. Here we show the cryo-electron microscopy structure of VMAT2 in the substrate-free state, in complex with the neurotransmitter dopamine, and in complex with the inhibitor tetrabenazine. In addition to these structural determinations, monoamine uptake assays, mutational studies, and pKa value predictions were performed to characterize the dynamic changes in VMAT2 structure. These results provide a structural basis for understanding VMAT2-mediated vesicular transport of neurotransmitters and a platform for modulation of current inhibitor design.

Suggested Citation

  • Dohyun Im & Mika Jormakka & Narinobu Juge & Jun-ichi Kishikawa & Takayuki Kato & Yukihiko Sugita & Takeshi Noda & Tomoko Uemura & Yuki Shiimura & Takaaki Miyaji & Hidetsugu Asada & So Iwata, 2024. "Neurotransmitter recognition by human vesicular monoamine transporter 2," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51960-z
    DOI: 10.1038/s41467-024-51960-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-51960-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-51960-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Joanne L. Parker & Justin C. Deme & Gabriel Kuteyi & Zhiyi Wu & Jiandong Huo & I. David Goldman & Raymond J. Owens & Philip C. Biggin & Susan M. Lea & Simon Newstead, 2021. "Structural basis of antifolate recognition and transport by PCFT," Nature, Nature, vol. 595(7865), pages 130-134, July.
    3. Dong Deng & Pengcheng Sun & Chuangye Yan & Meng Ke & Xin Jiang & Lei Xiong & Wenlin Ren & Kunio Hirata & Masaki Yamamoto & Shilong Fan & Nieng Yan, 2015. "Molecular basis of ligand recognition and transport by glucose transporters," Nature, Nature, vol. 526(7573), pages 391-396, October.
    4. Reiya Taniguchi & Hideaki E. Kato & Josep Font & Chandrika N. Deshpande & Miki Wada & Koichi Ito & Ryuichiro Ishitani & Mika Jormakka & Osamu Nureki, 2015. "Outward- and inward-facing structures of a putative bacterial transition-metal transporter with homology to ferroportin," Nature Communications, Nature, vol. 6(1), pages 1-10, December.
    5. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    6. Shabareesh Pidathala & Shuyun Liao & Yaxin Dai & Xiao Li & Changkun Long & Chi-Lun Chang & Zhe Zhang & Chia-Hsueh Lee, 2023. "Mechanisms of neurotransmitter transport and drug inhibition in human VMAT2," Nature, Nature, vol. 623(7989), pages 1086-1092, November.
    7. Kevin H. Wang & Aravind Penmatsa & Eric Gouaux, 2015. "Neurotransmitter and psychostimulant recognition by the dopamine transporter," Nature, Nature, vol. 521(7552), pages 322-327, May.
    8. Dohyun Im & Asuka Inoue & Takaaki Fujiwara & Takanori Nakane & Yasuaki Yamanaka & Tomoko Uemura & Chihiro Mori & Yuki Shiimura & Kanako Terakado Kimura & Hidetsugu Asada & Norimichi Nomura & Tomoyuki , 2020. "Structure of the dopamine D2 receptor in complex with the antipsychotic drug spiperone," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    9. Dohyun Im & Jun-ichi Kishikawa & Yuki Shiimura & Hiromi Hisano & Akane Ito & Yoko Fujita-Fujiharu & Yukihiko Sugita & Takeshi Noda & Takayuki Kato & Hidetsugu Asada & So Iwata, 2023. "Structural insights into the agonists binding and receptor selectivity of human histamine H4 receptor," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    10. Peter Aasted Paulsen & Tânia F. Custódio & Bjørn Panyella Pedersen, 2019. "Crystal structure of the plant symporter STP10 illuminates sugar uptake mechanism in monosaccharide transporter superfamily," Nature Communications, Nature, vol. 10(1), pages 1-8, December.
    11. Di Wu & Qihao Chen & Zhuoya Yu & Bo Huang & Jun Zhao & Yuhang Wang & Jiawei Su & Feng Zhou & Rui Yan & Na Li & Yan Zhao & Daohua Jiang, 2024. "Transport and inhibition mechanisms of human VMAT2," Nature, Nature, vol. 626(7998), pages 427-434, February.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yi C. Zeng & Meghna Sobti & Ada Quinn & Nicola J. Smith & Simon H. J. Brown & Jamie I. Vandenberg & Renae M. Ryan & Megan L. O’Mara & Alastair G. Stewart, 2023. "Structural basis of promiscuous substrate transport by Organic Cation Transporter 1," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    2. Lei Wang & Jiangguo Zhang & Dali Wang & Chen Song, 2022. "Membrane contact probability: An essential and predictive character for the structural and functional studies of membrane proteins," PLOS Computational Biology, Public Library of Science, vol. 18(3), pages 1-27, March.
    3. Sille Remm & Dario Vecchis & Jendrik Schöppe & Cedric A. J. Hutter & Imre Gonda & Michael Hohl & Simon Newstead & Lars V. Schäfer & Markus A. Seeger, 2023. "Structural basis for triacylglyceride extraction from mycobacterial inner membrane by MFS transporter Rv1410," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Yafei Yuan & Fang Kong & Hanwen Xu & Angqi Zhu & Nieng Yan & Chuangye Yan, 2022. "Cryo-EM structure of human glucose transporter GLUT4," Nature Communications, Nature, vol. 13(1), pages 1-8, December.
    6. Elisabeth Lambert & Ahmad Reza Mehdipour & Alexander Schmidt & Gerhard Hummer & Camilo Perez, 2022. "Evidence for a trap-and-flip mechanism in a proton-dependent lipid transporter," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    7. Ying Lyu & Chunting Fu & Haiyun Ma & Zhaoming Su & Ziyi Sun & Xiaoming Zhou, 2024. "Engineering of a mammalian VMAT2 for cryo-EM analysis results in non-canonical protein folding," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    8. Pierre Azoulay & Joshua Krieger & Abhishek Nagaraj, 2024. "Old Moats for New Models: Openness, Control, and Competition in Generative AI," NBER Chapters, in: Entrepreneurship and Innovation Policy and the Economy, volume 4, National Bureau of Economic Research, Inc.
    9. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    10. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    11. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Efren Garcia-Maldonado & Andrew D. Huber & Sergio C. Chai & Stanley Nithianantham & Yongtao Li & Jing Wu & Shyaron Poudel & Darcie J. Miller & Jayaraman Seetharaman & Taosheng Chen, 2024. "Chemical manipulation of an activation/inhibition switch in the nuclear receptor PXR," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    13. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    14. Katherine A. Ray & Joshua D. Lutgens & Ramesh Bista & Jie Zhang & Ronak R. Desai & Melissa Hirsch & Takeshi Miyazawa & Antonio Cordova & Adrian T. Keatinge-Clay, 2024. "Assessing and harnessing updated polyketide synthase modules through combinatorial engineering," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    15. Fan Lu & Liang Zhu & Thomas Bromberger & Jun Yang & Qiannan Yang & Jianmin Liu & Edward F. Plow & Markus Moser & Jun Qin, 2022. "Mechanism of integrin activation by talin and its cooperation with kindlin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    16. Zengyu Shao & Jiuwei Lu & Nelli Khudaverdyan & Jikui Song, 2024. "Multi-layered heterochromatin interaction as a switch for DIM2-mediated DNA methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    17. Yudong Gao & Daichi Shonai & Matthew Trn & Jieqing Zhao & Erik J. Soderblom & S. Alexandra Garcia-Moreno & Charles A. Gersbach & William C. Wetsel & Geraldine Dawson & Dmitry Velmeshev & Yong-hui Jian, 2024. "Proximity analysis of native proteomes reveals phenotypic modifiers in a mouse model of autism and related neurodevelopmental conditions," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    18. Martin F. Peter & Christian Gebhardt & Rebecca Mächtel & Gabriel G. Moya Muñoz & Janin Glaenzer & Alessandra Narducci & Gavin H. Thomas & Thorben Cordes & Gregor Hagelueken, 2022. "Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    19. Jutta Diessl & Jens Berndtsson & Filomena Broeskamp & Lukas Habernig & Verena Kohler & Carmela Vazquez-Calvo & Arpita Nandy & Carlotta Peselj & Sofia Drobysheva & Ludovic Pelosi & F.-Nora Vögtle & Fab, 2022. "Manganese-driven CoQ deficiency," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    20. Alexander Kroll & Sahasra Ranjan & Martin K. M. Engqvist & Martin J. Lercher, 2023. "A general model to predict small molecule substrates of enzymes based on machine and deep learning," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51960-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.