Structure of Murine CTLA-4 and Its Role in Modulating T Cell Responsiveness

Ostrov, David A.; Shi, Wuxian; Schwartz, Jean-Claude D.; Almo, Steven C.; Nathenson, Stanley G.

doi:10.1126/science.290.5492.816

Cited by 129 publications

(102 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Homodimeric structures have been observed in a number of other Ig superfamily proteins (41)(42)(43)(44)(45), but only one of these proteins, CD2, forms dimers via the GFCCЈ ␤-sheet of D1 (45,46). However, it is noteworthy that several Ig superfamily receptors engage viral ligands via the GFCCЈ ␤-sheet.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of human junctional adhesion molecule 1: Implications for reovirus binding

Prota

Campbell

Schelling

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

146

206

View full text Add to dashboard Cite

Reovirus attachment to cells is mediated by the binding of viral attachment protein 1 to junctional adhesion molecule 1 (JAM1). The crystal structure of the extracellular region of human JAM1 (hJAM1) reveals two concatenated Ig-type domains with a pronounced bend at the domain interface. Two hJAM1 molecules form a dimer that is stabilized by extensive ionic and hydrophobic contacts between the N-terminal domains. This dimeric arrangement is similar to that observed previously in the murine homolog of JAM1, indicating physiologic relevance. However, differences in the dimeric structures of hJAM1 and murine JAM1 suggest that the interface is dynamic, perhaps as a result of its ionic nature. We demonstrate that hJAM1, but not the related proteins hJAM2 and hJAM3, serves as a reovirus receptor, which provides insight into sites in hJAM1 that likely interact with 1. In addition, we present evidence that the previously reported structural homology between 1 and the adenovirus attachment protein, fiber, also extends to their respective receptors, which form similar dimeric structures. Because both receptors are located at regions of cellcell contact, this similarity suggests that reovirus and adenovirus use conserved mechanisms of entry and pathways of infection.

show abstract

Section: Resultsmentioning

confidence: 99%

Crystal structure of human junctional adhesion molecule 1: Implications for reovirus binding

Prota

Campbell

Schelling

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

146

206

View full text Add to dashboard Cite

show abstract

“…This prediction system maps the query sequence onto selected templates and extracts homology derived spatial constraints based on interatomic distances and dihedral angles to generate protein three-dimensional structures by "topology mapping" (18). The free mouse CD152 (Protein Data Bank code 1DQT chain A) (19) and human CD152 (Protein Data Bank code 1AH1) (20) and ligand-bound human CD152 (Protein Data Bank code 1I8L chain C and Protein Data Bank code 1I85 chain D) (12,21) were selected as the templates for modeling. The overlap for the secondary structure comparison of the modified CD152 queries and the three templates was between 51 and 67%.…”

Section: Methodsmentioning

confidence: 99%

“…This may be attributed to the lower potential of aromatic amino acids to propagate PP II helix (36). Integrating the residue preferences and propensities, novel CD80-CAP hexapeptides were designed so as to possess significant PP II helical content in the context of the CD80 binding interface.Substituting the CD80-CAP residues for the hydrophobic motif in the mouse CD152, comparative modeling of the modified CD152 was performed using the mouse CD152 (Protein Data Bank code 1DQT) as template (19,20). This gives a structural representation of the CD80-CAP with reference to the adjacent residues of CD152.…”

mentioning

confidence: 99%

CD80 Binding Polyproline Helical Peptide Inhibits T Cell Activation

Srinivasan

Eri

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

The critical role played by the CD28/CD152-CD80/ CD86 costimulatory molecules in mediating T cell activation and suppression provides attractive targets for therapeutic strategies. CD28 and CD152 share a conserved polyproline motif in the ligand-binding region. Similar proline-rich regions in globular domains preferentially adopt a polyproline type II (PP II ) helical conformation and are involved in transient protein-protein interactions. Interestingly, in the human CD80-CD152 complex, Pro 102 of CD152 restricts the preceding proline to PP II helix in the binding orientation in relation to the shallow binding pocket of CD80. Peptide agents derived from binding sites of receptors that mimic the bioactive conformation have been shown to block receptor-ligand interactions. Contact preferences of the interface amino acids at the protein-protein interaction sites and the propensity of each residue to form PP II helix were integrated in the design of novel peptide agents referred to as CD80 competitive antagonist peptides. Structural and functional studies suggest potential therapeutic value for select CD80 competitive antagonist peptides.The interaction between cell surface costimulatory molecules on antigen-presenting cells and the T cells is critical in modulating cell-cell communication (1). Two structurally and functionally well characterized T cell surface costimulatory molecules are CD28 and the CTLA4 (cytotoxic T lymphocyteassociated antigen)/CD152, both of which bind the same ligands, CD80 (B7-1) and CD86 (B7-2), on the antigen-presenting cells. Whereas signaling via CD28 mediates T cell activation, ligation of CD152 down-regulates T cell proliferation and function (2). Thus, CD80/CD86-CD28/CD152 costimulatory molecules are potential therapeutic targets for modulating T cell responses.Analyses of multiple receptor-ligand interactions suggest that in exposed domains involved in protein-protein interactions that mediate cell signaling, the intermolecular interfaces often present extended shallow clefts on ligand surfaces (3). Hence, molecules whose shapes complement the protein interaction clefts of the ligand surfaces are likely to block receptor binding (4). Previously, several linear peptides with extended polyproline type II (PP II ) 1 conformation have been shown to block ligand-acceptor complexes involved in molecular recognition (5-7). Acceptors are typically large proteins with measurable affinity for specific ligands; the latter can be presented as a small peptide sequence within an exposed loop on the surface of a large protein. Structurally, ligands may exist in extended PP II helical conformation, allowing the backbone atoms of the peptide to form hydrogen bonds with protein acceptor at the interface of the protein-peptide complex (8, 9). Examples of complexes where the ligand is in PP II conformation include the EFPPPPT peptide, which interacts with the VASP (vasodilator-stimulated phosphoprotein) EVH1 (Ena/VASP homology) domain (Protein Data Bank code 1QC6), and the SOS (Son of Sevenless) peptide...

show abstract

“…On the other hand, the interaction of B7.1/B7.2 molecules with CTLA-4 expressed on T-cells induced an inhibitory signal for down-regulation of T-cell functions. CTLA-4, which is one of the CD28 homologues, does not exist on resting T-cells, however, it is expressed following T-cell activation (Ostrov et al, 2000). Thus, the balance between opposing signals elicited by CD28 and CTLA-4 is very important for regulation of T-cell responsiveness.…”

Section: Introductionmentioning

confidence: 99%

“…CTLA-4 has received attention as a therapeutic agent due to its modulating role in T-cell activity. CTLA4-Ig has been used as an inhibitor of CD28-B7.1/ B7.2 binding for the treatment of autoimmune diseases, transplant rejection, and hypersensitiveness in animal models (Ostrov et al, 2000;Park et al, 2003). Although CTLA4-Ig blocks co-stimulatory receptors on the surface of APCs, the molecular events inside APCs induced by their binding are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

Effects of Anti-B7.1/B7.2 Antibodies on LPS-Stimulated Macrophages

Won¹,

Huh²,

Lim³

et al. 2010

Biomolecules and Therapeutics

View full text Add to dashboard Cite

-T-cell activation depends on signals received by the T-cell receptor and CD28 co-stimulatory receptor. Since B7.1 and B7.2 molecules expressed on the surface of antigen presenting cells provide co-stimulatory signals through CD28 to T-cells, an inhibitor of CD28-B7.1/B7.2 binding has been proposed as a therapeutic agent for suppression of excessive T-cell activity. Although anti-B7.1/B7.2 antibodies are known to block B7.1 and B7.2 molecules, their effects on intracellular events in antigen presenting cells remain unclear. In this study, anti-B7.1/B7.2 antibodies decreased secretion of nitric oxide and pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-12 in LPS-activated RAW264.7 macrophage-like cells and peritoneal macrophages. Moreover, anti-B7.1/B7.2 antibodies inhibited IκBα phosphorylation and down-regulated expression of co-stimulatory molecules including B7.1, B7.2, and PD-L1 in LPS-stimulated peritoneal macrophages. These findings suggest that CTLA4-Ig and anti-B7.1/B7.2 antibodies may be candidates to treat chronic inflammatory diseases and autoimmune responses caused by excessive activation of both T-cells and macrophages.

show abstract

Structure of Murine CTLA-4 and Its Role in Modulating T Cell Responsiveness

Cited by 129 publications

References 43 publications

Crystal structure of human junctional adhesion molecule 1: Implications for reovirus binding

Crystal structure of human junctional adhesion molecule 1: Implications for reovirus binding

CD80 Binding Polyproline Helical Peptide Inhibits T Cell Activation

Effects of Anti-B7.1/B7.2 Antibodies on LPS-Stimulated Macrophages

Contact Info

Product

Resources

About