title: T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface.
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 A 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.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Erhu
authors.initials: E
authors.lastname: Cao
authors.forename: Xingxing
authors.initials: X
authors.lastname: Zang
authors.forename: Udupi A
authors.initials: UA
authors.lastname: Ramagopal
authors.forename: Arunika
authors.initials: A
authors.lastname: Mukhopadhaya
authors.forename: Alexander
authors.initials: A
authors.lastname: Fedorov
authors.forename: Elena
authors.initials: E
authors.lastname: Fedorov
authors.forename: Wendy D
authors.initials: WD
authors.lastname: Zencheck
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Lary
authors.forename: James L
authors.initials: JL
authors.lastname: Cole
authors.forename: Haiteng
authors.initials: H
authors.lastname: Deng
authors.forename: Hui
authors.initials: H
authors.lastname: Xiao
authors.forename: Teresa P
authors.initials: TP
authors.lastname: Dilorenzo
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Stanley G
authors.initials: SG
authors.lastname: Nathenson
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D003545:Cysteine / Q000737:chemistry / Q000235:genetics; D037161:Galectins / Q000737:chemistry*; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011991:Receptors, Virus / Q000737:chemistry* / Q000235:genetics
chemical_list: D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D008024:Ligands; D011991:Receptors, Virus; C508186:galectin 9, mouse; D003545:Cysteine