IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-41756-y.html
   My bibliography  Save this article

Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE

Author

Listed:
  • Joann Chongsaritsinsuk

    (Yale University)

  • Alexandra D. Steigmeyer

    (Yale University)

  • Keira E. Mahoney

    (Yale University)

  • Mia A. Rosenfeld

    (University of California, San Diego)

  • Taryn M. Lucas

    (Yale University)

  • Courtney M. Smith

    (Yale University School of Medicine)

  • Alice Li

    (Yale University School of Medicine)

  • Deniz Ince

    (Yale University)

  • Fiona L. Kearns

    (University of California, San Diego)

  • Alexandria S. Battison

    (Yale University)

  • Marie A. Hollenhorst

    (Stanford University
    Stanford University
    Stanford University)

  • D. Judy Shon

    (Stanford University)

  • Katherine H. Tiemeyer

    (Stanford University)

  • Victor Attah

    (Yale University)

  • Catherine Kwon

    (Yale University)

  • Carolyn R. Bertozzi

    (Stanford University
    Stanford University)

  • Michael J. Ferracane

    (University of Redlands)

  • Mark A. Lemmon

    (Yale University School of Medicine)

  • Rommie E. Amaro

    (University of California, San Diego
    University of California, San Diego)

  • Stacy A. Malaker

    (Yale University)

Abstract

Mucin-domain glycoproteins are densely O-glycosylated and play critical roles in a host of biological functions. In particular, the T cell immunoglobulin and mucin-domain containing family of proteins (TIM-1, -3, -4) decorate immune cells and act as key regulators in cellular immunity. However, their dense O-glycosylation remains enigmatic, primarily due to the challenges associated with studying mucin domains. Here, we demonstrate that the mucinase SmE has a unique ability to cleave at residues bearing very complex glycans. SmE enables improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we perform molecular dynamics (MD) simulations of TIM-3 and -4 to understand how glycosylation affects structural features of these proteins. Finally, we use these models to investigate the functional relevance of glycosylation for TIM-3 function and ligand binding. Overall, we present a powerful workflow to better understand the detailed molecular structures and functions of the mucinome.

Suggested Citation

  • Joann Chongsaritsinsuk & Alexandra D. Steigmeyer & Keira E. Mahoney & Mia A. Rosenfeld & Taryn M. Lucas & Courtney M. Smith & Alice Li & Deniz Ince & Fiona L. Kearns & Alexandria S. Battison & Marie A, 2023. "Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41756-y
    DOI: 10.1038/s41467-023-41756-y
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-41756-y
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-41756-y?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. Rebecca Nason & Christian Büll & Andriana Konstantinidi & Lingbo Sun & Zilu Ye & Adnan Halim & Wenjuan Du & Daniel M. Sørensen & Fabien Durbesson & Sanae Furukawa & Ulla Mandel & Hiren J. Joshi & Leo , 2021. "Display of the human mucinome with defined O-glycans by gene engineered cells," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    2. 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.
    3. Beatriz Trastoy & Andreas Naegeli & Itxaso Anso & Jonathan Sjögren & Marcelo E. Guerin, 2020. "Structural basis of mammalian mucin processing by the human gut O-glycopeptidase OgpA from Akkermansia muciniphila," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    4. Chih-Hao Lu & Kayvon Pedram & Ching-Ting Tsai & Taylor Jones & Xiao Li & Melissa L. Nakamoto & Carolyn R. Bertozzi & Bianxiao Cui, 2022. "Membrane curvature regulates the spatial distribution of bulky glycoproteins," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    5. Stacy A. Malaker & Nicholas M. Riley & D. Judy Shon & Kayvon Pedram & Venkatesh Krishnan & Oliver Dorigo & Carolyn R. Bertozzi, 2022. "Revealing the human mucinome," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. N. Giovannone & J. Liang & A. Antonopoulos & J. Geddes Sweeney & S. L. King & S. M. Pochebit & N. Bhattacharyya & G. S. Lee & A. Dell & H. R. Widlund & S. M. Haslam & C. J. Dimitroff, 2018. "Galectin-9 suppresses B cell receptor signaling and is regulated by I-branching of N-glycans," Nature Communications, Nature, vol. 9(1), pages 1-17, December.
    7. Edward Jenkins & Markus Körbel & Caitlin O’Brien-Ball & James McColl & Kevin Y. Chen & Mateusz Kotowski & Jane Humphrey & Anna H. Lippert & Heather Brouwer & Ana Mafalda Santos & Steven F. Lee & Simon, 2023. "Antigen discrimination by T cells relies on size-constrained microvillar contact," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    8. Anh Cao & Nouf Alluqmani & Fatima Hifza Mohammed Buhari & Laabiah Wasim & Logan K. Smith & Andrew T. Quaile & Michael Shannon & Zaki Hakim & Hossai Furmli & Dylan M. Owen & Alexei Savchenko & Bebhinn , 2018. "Galectin-9 binds IgM-BCR to regulate B cell signaling," Nature Communications, Nature, vol. 9(1), pages 1-18, December.
    9. 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.
    10. Riyao Yang & Linlin Sun & Ching-Fei Li & Yu-Han Wang & Jun Yao & Hui Li & Meisi Yan & Wei-Chao Chang & Jung-Mao Hsu & Jong-Ho Cha & Jennifer L. Hsu & Cheng-Wei Chou & Xian Sun & Yalan Deng & Chao-Kai , 2021. "Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    11. Masanori Miyanishi & Kazutoshi Tada & Masato Koike & Yasuo Uchiyama & Toshio Kitamura & Shigekazu Nagata, 2007. "Identification of Tim4 as a phosphatidylserine receptor," Nature, Nature, vol. 450(7168), pages 435-439, November.
    12. Víctor Taleb & Qinghua Liao & Yoshiki Narimatsu & Ana García-García & Ismael Compañón & Rafael Junqueira Borges & Andrés Manuel González-Ramírez & Francisco Corzana & Henrik Clausen & Carme Rovira & R, 2022. "Structural and mechanistic insights into the cleavage of clustered O-glycan patches-containing glycoproteins by mucinases of the human gut," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    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. Bashar Shuoker & Michael J. Pichler & Chunsheng Jin & Hiroka Sakanaka & Haiyang Wu & Ana Martínez Gascueña & Jining Liu & Tine Sofie Nielsen & Jan Holgersson & Eva Nordberg Karlsson & Nathalie Juge & , 2023. "Sialidases and fucosidases of Akkermansia muciniphila are crucial for growth on mucin and nutrient sharing with mucus-associated gut bacteria," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Ye Yuan & Lei Chen & Kexu Song & Miaomiao Cheng & Ling Fang & Lingfei Kong & Lanlan Yu & Ruonan Wang & Zhendong Fu & Minmin Sun & Qian Wang & Chengjun Cui & Haojue Wang & Jiuyang He & Xiaonan Wang & Y, 2024. "Stable peptide-assembled nanozyme mimicking dual antifungal actions," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Ivica Odorčić & Mohamed Belal Hamed & Sam Lismont & Lucía Chávez-Gutiérrez & Rouslan G. Efremov, 2024. "Apo and Aβ46-bound γ-secretase structures provide insights into amyloid-β processing by the APH-1B isoform," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    4. Stella Vitt & Simone Prinz & Martin Eisinger & Ulrich Ermler & Wolfgang Buckel, 2022. "Purification and structural characterization of the Na+-translocating ferredoxin: NAD+ reductase (Rnf) complex of Clostridium tetanomorphum," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. 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.
    6. Riya Shah & Thomas C. Panagiotou & Gregory B. Cole & Trevor F. Moraes & Brigitte D. Lavoie & Christopher A. McCulloch & Andrew Wilde, 2024. "The DIAPH3 linker specifies a β-actin network that maintains RhoA and Myosin-II at the cytokinetic furrow," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Yashan Yang & Qianqian Shao & Mingcheng Guo & Lin Han & Xinyue Zhao & Aohan Wang & Xiangyun Li & Bo Wang & Ji-An Pan & Zhenguo Chen & Andrei Fokine & Lei Sun & Qianglin Fang, 2024. "Capsid structure of bacteriophage ΦKZ provides insights into assembly and stabilization of jumbo phages," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    8. Bret M. Boyd & Ian James & Kevin P. Johnson & Robert B. Weiss & Sarah E. Bush & Dale H. Clayton & Colin Dale, 2024. "Stochasticity, determinism, and contingency shape genome evolution of endosymbiotic bacteria," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Jun-Yu Si & Yuan-Mei Chen & Ye-Hui Sun & Meng-Xue Gu & Mei-Ling Huang & Lu-Lu Shi & Xiao Yu & Xiao Yang & Qing Xiong & Cheng-Bao Ma & Peng Liu & Zheng-Li Shi & Huan Yan, 2024. "Sarbecovirus RBD indels and specific residues dictating multi-species ACE2 adaptiveness," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    10. 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.
    11. 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.
    12. Justin N. Vaughn & Sandra E. Branham & Brian Abernathy & Amanda M. Hulse-Kemp & Adam R. Rivers & Amnon Levi & William P. Wechter, 2022. "Graph-based pangenomics maximizes genotyping density and reveals structural impacts on fungal resistance in melon," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    13. Eliza S. Nieweglowska & Axel F. Brilot & Melissa Méndez-Moran & Claire Kokontis & Minkyung Baek & Junrui Li & Yifan Cheng & David Baker & Joseph Bondy-Denomy & David A. Agard, 2023. "The ϕPA3 phage nucleus is enclosed by a self-assembling 2D crystalline lattice," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    14. Sash Lopaticki & Robyn McConville & Alan John & Niall Geoghegan & Shihab Deen Mohamed & Lisa Verzier & Ryan W. J. Steel & Cindy Evelyn & Matthew T. O’Neill & Niccolay Madiedo Soler & Nichollas E. Scot, 2022. "Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    15. Radoslaw Pluta & Eric Aragón & Nicholas A. Prescott & Lidia Ruiz & Rebeca A. Mees & Blazej Baginski & Julia R. Flood & Pau Martin-Malpartida & Joan Massagué & Yael David & Maria J. Macias, 2022. "Molecular basis for DNA recognition by the maternal pioneer transcription factor FoxH1," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Xinheng He & Lifen Zhao & Yinping Tian & Rui Li & Qinyu Chu & Zhiyong Gu & Mingyue Zheng & Yusong Wang & Shaoning Li & Hualiang Jiang & Yi Jiang & Liuqing Wen & Dingyan Wang & Xi Cheng, 2024. "Highly accurate carbohydrate-binding site prediction with DeepGlycanSite," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    17. 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.
    18. 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.
    19. Mindaugas Margelevičius, 2024. "GTalign: spatial index-driven protein structure alignment, superposition, and search," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    20. 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.

    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:14:y:2023:i:1:d:10.1038_s41467-023-41756-y. 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.