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PDBsum entry 2oyp
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Signaling protein
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PDB id
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2oyp
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References listed in PDB file
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Key reference
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Title
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T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-Independent ligand-Binding surface.
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Authors
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E.Cao,
X.Zang,
U.A.Ramagopal,
A.Mukhopadhaya,
A.Fedorov,
E.Fedorov,
W.D.Zencheck,
J.W.Lary,
J.L.Cole,
H.Deng,
H.Xiao,
T.P.Dilorenzo,
J.P.Allison,
S.G.Nathenson,
S.C.Almo.
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Ref.
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Immunity, 2007,
26,
311-321.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 1.
Figure 1. Murine Tim-3 IgV Domain Exists as a Monomer in
Solution
(A) Elution profile of the Tim-3 IgV domain from
Superdex G75 column. The single monodisperse peak at 14.9 ml is
consistent with the predicted behavior of Tim-3 monomer.
(B) g(s^*) analysis of Tim-3 IgV domain. The protein
concentration ranges from 0.15 to 1.51 mg/ml.
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Figure 2.
Figure 2. Tim-3 Possesses a Unique Modification of the
Immunoglobulin Domain
(A) Comparison of murine Tim-3 IgV
domain and classical IgV domain. Left, ribbon diagram of murine
PD-1 structure (1NPU), showing the classical IgV fold in which
CC′ and FG loops are located at the opposite ends of the
domain (Zhang et al., 2004). Middle, overall structure of Tim-3
IgV, showing the “cleft” formed by the CC′ and FG loops.
Right, expanded view of the cleft, detailing the stabilizing
interactions. The β strands are labeled with capital letters.
Disulfide bonds are represented by green sticks, and four
additional cysteines that form two extra intramolecular
disulfide bonds in the cleft are labeled. Residues involved in
hydrogen bonding and ionic interactions are denoted as sticks
and are labeled. The hydrogen bonds and salt bridge are
highlighted by red dash lines.
(B) Alignment of the IgV
domain sequences of Tim family members. The β strands are
denoted as underlined segments in murine Tim-3. The conserved
residues are shaded red, and residues with similar properties
are labeled red. Six invariant cysteines within the family are
labeled. Three pairs of cysteines, i.e., Cys-38 and Cys-111
(black), Cys-52 and Cys-63 (blue), and Cys-58 and Cys-110 (red),
form three disulfide bonds. Residues bearing potential N- and
O-glycans are highlighted with a blue triangle and numbered.
Residues that contribute to ligand binding of Tim-3 are
highlighted with pink triangle and numbered.
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The above figures are
reprinted
by permission from Cell Press:
Immunity
(2007,
26,
311-321)
copyright 2007.
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