T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface.
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.
Cao
Erhu
E
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Zang
Xingxing
X
Ramagopal
Udupi A
UA
Mukhopadhaya
Arunika
A
Fedorov
Alexander
A
Fedorov
Elena
E
Zencheck
Wendy D
WD
Lary
Jeffrey W
JW
Cole
James L
JL
Deng
Haiteng
H
Xiao
Hui
H
Dilorenzo
Teresa P
TP
Allison
James P
JP
Nathenson
Stanley G
SG
Almo
Steven C
SC
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
D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D008024:Ligands; D011991:Receptors, Virus; C508186:galectin 9, mouse; D003545:Cysteine