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Glycoproteomic landscape and structural dynamics of TIM family immune checkpoints enabled by mucinase SmE.
Chongsaritsinsuk, Joann; Steigmeyer, Alexandra D; Mahoney, Keira E; Rosenfeld, Mia A; Lucas, Taryn M; Ince, Deniz; Kearns, Fiona L; Battison, Alexandria S; Hollenhorst, Marie A; Shon, D Judy; Tiemeyer, Katherine H; Attah, Victor; Kwon, Catherine; Bertozzi, Carolyn R; Ferracane, Michael J; Amaro, Rommie E; Malaker, Stacy A.
Afiliación
  • Chongsaritsinsuk J; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Steigmeyer AD; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Mahoney KE; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Rosenfeld MA; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • Lucas TM; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Ince D; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Kearns FL; Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA.
  • Battison AS; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Hollenhorst MA; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • Shon DJ; Department of Pathology, Stanford University, Stanford, CA 94305, USA.
  • Tiemeyer KH; Department of Medicine, Division of Hematology, Stanford University, Stanford, CA 94305, USA.
  • Attah V; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • Kwon C; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • Bertozzi CR; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Ferracane MJ; Department of Chemistry, Yale University, New Haven, CT 06511, USA.
  • Amaro RE; Department of Chemistry and Sarafan ChEM-H, Stanford University, Stanford, CA 94305, USA.
  • Malaker SA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
bioRxiv ; 2023 Feb 03.
Article en En | MEDLINE | ID: mdl-36778266
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 checkpoint inhibitors in cancer. However, their dense O-glycosylation remains enigmatic both in terms of glycoproteomic landscape and structural dynamics, primarily due to the challenges associated with studying mucin domains. Here, we present a mucinase (SmE) and demonstrate its ability to selectively cleave along the mucin glycoprotein backbone, similar to others of its kind. Unlike other mucinases, though, SmE harbors the unique ability to cleave at residues bearing extremely complex glycans which enabled improved mass spectrometric analysis of several mucins, including the entire TIM family. With this information in-hand, we performed molecular dynamics (MD) simulations of TIM-3 and -4 to demonstrate how glycosylation affects structural features of these proteins. Overall, we present a powerful workflow to better understand the detailed molecular structures of the mucinome.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Añadir a Mi BVS
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XML
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: BioRxiv Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos