PDBsum entry 2or7

Immune system

PDB id: 2or7

Contents

Protein chains

107 a.a.

115 a.a.

Ligands

ACT

Waters ×126

References listed in PDB file

Key reference

Title

Structures of t cell immunoglobulin mucin receptors 1 and 2 reveal mechanisms for regulation of immune responses by the tim receptor family.

Authors

C.Santiago, A.Ballesteros, C.Tami, L.Martínez-Muñoz, G.G.Kaplan, J.M.Casasnovas.

Ref.

Immunity, 2007, 26, 299-310. [DOI no: 10.1016/j.immuni.2007.01.014]

PubMed id

17363299

Abstract

The T cell immunoglobulin mucin (TIM) receptors are involved in the regulation of immune responses, autoimmunity, and allergy. Structures of the N-terminal ligand binding domain of the murine mTIM-1 and mTIM-2 receptors revealed an immunoglobulin (Ig) fold, with four Cys residues bridging a distinctive CC' loop to the GFC beta-sheet. The structures showed two ligand-recognition modes in the TIM family. The mTIM-1 structure identified a homophilic TIM-TIM adhesion interaction, whereas the mTIM-2 domain formed a dimer that prevented homophilic binding. Biochemical, mutational, and cell adhesion analyses confirmed the divergent ligand-binding modes revealed by the structures. Structural features characteristic of mTIM-1 appear conserved in human TIM-1, which also mediated homophilic interactions. The extracellular mucin domain enhanced binding through the Ig domain, modulating TIM receptor functions. These results explain the divergent immune functions described for the murine receptors and the role of TIM-1 as a cell adhesion receptor in renal regeneration and cancer.

Figure 3.
Figure 3. N-Terminal Domain Interactions in the TIM Receptors
(A and B) Ribbon diagrams of the two domains in the asymmetric unit of the mTIM-2 (A) and mTIM-1 (B) crystals. Side view of the dimer is displayed for mTIM-2, whereas a view along the quasi-2-fold axis (2) is shown for mTIM-1. Molecules presented in Figure 1 have the same coloring scheme, and the neighboring molecules are in yellow. Side chains of residues contributing to the dimer interfaces are included and some central residues are labeled. Acetate ligand found in the mTIM-2 structure is black, water molecules are red spheres, and hydrogen bonds are pink dashed cylinders. Asn residues to which glycans link in mTIM-2 are green. Arrows represent the hypothetical interaction of O-linked glycans from the C-terminal mucin domain with residues at the β strand A, BC, and FG loops of the interacting mTIM-1 domains (see also Figure S3).
(C) Self-association of the N-terminal IgV domains in solution. SDS-PAGE under reducing conditions of mTIM-1, mTIM-2, and mTIM-4 domains untreated (−) or treated with the indicated BS^3 crosslinker concentration (mM). Treated ICAM-1 protein (IC1-2D) known to dimerize at high concentration and a soluble fragment of CD46 are also included. Size and migration of the molecular weight marker is indicated. Crosslinked dimers are labeled with an asterisk. No dimerization of the mTIM-4 IgV domain is seen here or in the protein crystals (not shown).
(D) Structural alignment with residues at the dimer interface in yellow and those at the center of the interacting molecules in blue. β strands are represented by lines.

Figure 7.
Figure 7. Ligand-Binding Surfaces in the IgV Domain of TIM-1 Receptors
Surface representation of the mTIM-1 domain structure. Surface involved in the homophilic interaction is pink. Residues in a conformational epitope built by the tip of the long CC′ loop and the FG loop onto the GFC β sheet are colored red and orange, respectively. The surface where an mkTIM-1 polymorphism (Lys88Gln) has been mapped is in blue. The mutation identified the side of the domain recognized by a mAb blocking HAV binding to its mkTIM-1 receptor (Feigelstock et al., 1998a). Surface corresponding to the Asn residue to which glycans will be linked in the primate TIM-1 receptors is green.

The above figures are reprinted by permission from Cell Press: Immunity (2007, 26, 299-310) copyright 2007.