T Cell Immunoglobulin Mucin-3 Crystal Structure Reveals a Galectin-9-Independent Ligand-Binding Surface

Erhu Cao, Xingxing Zang, Udupi A. Ramagopal, Arunika Mukhopadhaya, Alexander Fedorov, Elena Fedorov, Wendy D. Zencheck, Jeffrey W. Lary, James L. Cole, Haiteng Deng, Hui Xiao, Teresa P. DiLorenzo, James P. Allison, Stanley G. Nathenson, Steven C. Almo

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

The T cell immunoglobulin mucin (Tim) family of receptors regulates effector CD4+ T cell functions and is implicated in autoimmune and allergic diseases. Tim-3 induces immunological tolerance, and engagement of the Tim-3 immunoglobulin variable (IgV) domain by galectin-9 is important for appropriate termination of T helper 1-immune responses. The 2 Å crystal structure of the Tim-3 IgV domain demonstrated that four cysteines, which are invariant within the Tim family, form two noncanonical disulfide bonds, resulting in a surface not present in other immunoglobulin superfamily members. Biochemical and biophysical studies demonstrated that this unique structural feature mediates a previously unidentified galectin-9-independent binding process and suggested that this structural feature is conserved within the entire Tim family. The current work provided a graphic example of the relationship between sequence, structure, and function and suggested that the interplay between multiple Tim-3-binding activities contributes to the regulated assembly of signaling complexes required for effective Th1-mediated immunity.

Original languageEnglish (US)
Pages (from-to)311-321
Number of pages11
JournalImmunity
Volume26
Issue number3
DOIs
StatePublished - Mar 23 2007

Keywords

  • HUMDISEASE
  • MOLIMMUNO
  • SIGNALING

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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    Cao, E., Zang, X., Ramagopal, U. A., Mukhopadhaya, A., Fedorov, A., Fedorov, E., Zencheck, W. D., Lary, J. W., Cole, J. L., Deng, H., Xiao, H., DiLorenzo, T. P., Allison, J. P., Nathenson, S. G., & Almo, S. C. (2007). T Cell Immunoglobulin Mucin-3 Crystal Structure Reveals a Galectin-9-Independent Ligand-Binding Surface. Immunity, 26(3), 311-321. https://doi.org/10.1016/j.immuni.2007.01.016