PDBsum entry 2oyp

Signaling protein

PDB id: 2oyp

Contents

Protein chain

109 a.a. *

Ligands

SO4

Waters ×96

* Residue conservation analysis

PDB id:

2oyp

Name:

Signaling protein

Title:

T cell immunoglobulin mucin-3 crystal structure revealed a galectin-9- independent binding surface

Structure:

Hepatitis a virus cellular receptor 2. Chain: a. Fragment: immunoglobulin v-set. Engineered: yes

Source:

Mus musculus. House mouse. Organism_taxid: 10090. Strain: balb/c. Gene: havcr2. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

1.95Å R-factor: 0.158 R-free: 0.200

Authors:

E.Cao,U.A.Ramagopal,A.A.Fedorov,E.V.Fedorov,S.G.Nathenson,S.C.Almo

Key ref:

E.Cao et al. (2007). T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface. Immunity, 26, 311-321. PubMed id: 17363302 DOI: 10.1016/j.immuni.2007.01.016

Date:

22-Feb-07 Release date: 10-Apr-07

Protein chain

Q3KP82  (Q3KP82_MOUSE) -  Hepatitis A virus cellular receptor 2 from Mus musculus

Seq: 281 a.a.

Struc: 109 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1016/j.immuni.2007.01.016

Immunity 26:311-321 (2007)

PubMed id: 17363302

T cell immunoglobulin mucin-3 crystal structure reveals a galectin-9-independent ligand-binding surface.

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.

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.

Selected figure(s)

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.

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.

The above figures are reprinted by permission from Cell Press: Immunity (2007, 26, 311-321) copyright 2007.

Figures were selected by an automated process.