Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15 Å

Zajonc, Dirk M.; Elsliger, Marc‐André; Teyton, Luc; Wilson, Ian A.

doi:10.1038/ni948

Cited by 216 publications

(242 citation statements)

References 48 publications

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“…3B), PI 3-kinase, or possibly other proteins. Consistent with the earlier reports (39,40), it is likely that under these conditions the binding groove of mCD1d protein might be more exposed to solvent resulting in better binding of lyso-sulfatide. Though our in vitro binding studies to plate-bound CD1d (Fig.…”

Section: Discussionsupporting

confidence: 89%

Involvement of Secretory and Endosomal Compartments in Presentation of an Exogenous Self-Glycolipid to Type II NKT Cells

Roy

Maricic

Khurana

et al. 2008

The Journal of Immunology

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Natural Killer T (NKT) cells recognize both self and foreign lipid Ags presented by CD1 molecules. Although presentation of the marine sponge-derived lipid αGalCer to type I NKT cells has been well studied, little is known about self-glycolipid presentation to either type I or type II NKT cells. Here we have investigated presentation of the self-glycolipid sulfatide to a type II NKT cell that specifically recognizes a single species of sulfatide, namely lyso-sulfatide but not other sulfatides containing additional acyl chains. In comparison to other sulfatides or αGalCer, lyso-sulfatide binds with lower affinity to CD1d. Although plate-bound CD1d is inefficient in presenting lyso-sulfatide at neutral pH, it is efficiently presented at acidic pH and in the presence of saposin C. The lysosomal trafficking of mCD1d is required for αGalCer presentation to type I NKT cells, it is not important for presentation of lyso-sulfatide to type II NKT cells. Consistently, APCs deficient in a lysosomal lipid-transfer protein effectively present lyso-sulfatide. Presentation of lyso-sulfatide is inhibited in the presence of primaquine, concanamycin A, monensin, cycloheximide, and an inhibitor of microsomal triglyceride transfer protein but remains unchanged following treatment with brefeldin A. Wortmannin-mediated inhibition of lipid presentation indicates an important role for the PI-3kinase in mCD1d trafficking. Our data collectively suggest that weak CD1d-binding self-glycolipid ligands such as lyso-sulfatide can be presented via the secretory and endosomal compartments. Thus this study provides important insights into the exogenous self-glycolipid presentation to CD1d-restricted T cells.

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Section: Discussionsupporting

confidence: 89%

Involvement of Secretory and Endosomal Compartments in Presentation of an Exogenous Self-Glycolipid to Type II NKT Cells

Roy

Maricic

Khurana

et al. 2008

The Journal of Immunology

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“…Various foreign ligands can activate iNKT cells, such as the nonmammalian glycolipid, ␣-galactosylceramide (␣-GalCer) (12), microbial ␣-glycuronosylceramides (13,14) (containing either glucuronic acid or galacturonic acid (GalA-GSL)), mycobacterial PIM4 (15), as well as the self-ligand isoglobotrihexosylceramide (iGB3) (16). Crystal structures of CD1d in complex with ␣-GalCer or GalA-GSL (17)(18)(19) have revealed the exquisite hydrogen-bonding network between the ␣-linked carbohydrate headgroup and CD1d, which has not been seen in any other CD1 complex, including human CD1a-sulfatide (20), CD1a-lipopeptide (21), CD1b-PI (22), CD1b-glucosemonomycolate (23), or mouse CD1d-phosphatidylcholine (CD1d-PC) (24).…”

mentioning

confidence: 99%

Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d

Zajonc

Ainge²,

Painter³

et al. 2006

The Journal of Immunology

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Mycobacterial phosphatidylinositol tetramannosides (PIM4) are agonists for a distinct population of invariant human (Vα24) and mouse (Vα14) NKT cells, when presented by CD1d. We determined the crystal structure at 2.6-Å resolution of mouse CD1d bound to a synthetic dipalmitoyl-PIM2. Natural PIM2, which differs in its fatty acid composition is a biosynthetic precursor of PIM4, PIM6, lipomannan, and lipoarabinomannan. The PIM2 headgroup (inositol-dimannoside) is the most complex to date among all the crystallized CD1d ligands and is remarkably ordered in the CD1d binding groove. A specific hydrogen-bonding network between PIM2 and CD1d orients the headgroup in the center of the binding groove and above the A′ pocket. A central cluster of hydrophilic CD1d residues (Asp153, Thr156, Ser76, Arg79) interacts with the phosphate, inositol, and α1–α6-linked mannose of the headgroup, whereas additional specificity for the α1- and α2-linked mannose is conferred by Thr159. The additional two mannoses in PIM4, relative to PIM2, are located at the distal 6′ carbon of the α1-α6-linked mannose and would project away from the CD1d binding groove for interaction with the TCR. Compared with other CD1d-sphingolipid structures, PIM2 has an increased number of polar interactions between its headgroup and CD1, but reduced specificity for the diacylglycerol backbone. Thus, novel NKT cell agonists can be designed that focus on substitutions of the headgroup rather than on reducing lipid chain length, as in OCH and PBS-25, two potent variants of the highly stimulatory invariant NKT cell agonist α-galactosylceramide.

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“…The solution of the 3D structures of CD1a, CD1b, and CD1d reveals that they resemble the classical peptide antigenpresenting MHC molecules (2)(3)(4). In contrast to MHC molecules, the antigen-binding groove of CD1 is large, exclusively nonpolar, and hydrophobic (2)(3)(4) and hence has evolved to chaperone lipid antigens to the cell surface.…”

mentioning

confidence: 99%

“…In contrast to MHC molecules, the antigen-binding groove of CD1 is large, exclusively nonpolar, and hydrophobic (2)(3)(4) and hence has evolved to chaperone lipid antigens to the cell surface. The majority of antigenic lipid binding to CD1 occurs within endocytic compartments (5)(6)(7)(8).…”

mentioning

confidence: 99%

Lipid–protein interactions: Biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved

Park

Kang

Silva

et al. 2004

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

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The CD1 family consists of lipid antigen-presenting molecules, which include group I CD1a, CD1b, and CD1c and group II CD1d proteins. Topologically, they resemble the classical peptide antigen-presenting MHC molecules except that the large, exclusively nonpolar and hydrophobic, antigen-binding groove of CD1 has evolved to present cellular and pathogen-derived lipid antigens to specific T lymphocytes. As an approach to understanding the biochemical basis of lipid antigen presentation by CD1 molecules, we have characterized the natural ligands associated with mouse CD1d1 as well as human CD1b and CD1d molecules. We found that both group I and II CD1 molecules assemble with cellular phosphatidylinositol (PI), which contains heterogeneous fatty acyl chains. Further, this assembly occurs within the endoplasmic reticulum. Because the structures of the antigen-binding grooves of CD1a and CD1c closely resemble those of CD1b and CD1d, we conclude that the assembly of CD1 molecules with PI in the endoplasmic reticulum is evolutionarily conserved. These findings suggest that PI plays a chaperone-like role in CD1 assembly, possibly to preserve the integrity of the antigen-binding groove until CD1 binds antigenic lipids in the endocytic pathway.

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Crystal structure of CD1a in complex with a sulfatide self antigen at a resolution of 2.15 Å

Cited by 216 publications

References 48 publications

Involvement of Secretory and Endosomal Compartments in Presentation of an Exogenous Self-Glycolipid to Type II NKT Cells

Involvement of Secretory and Endosomal Compartments in Presentation of an Exogenous Self-Glycolipid to Type II NKT Cells

Structural Characterization of Mycobacterial Phosphatidylinositol Mannoside Binding to Mouse CD1d

Lipid–protein interactions: Biosynthetic assembly of CD1 with lipids in the endoplasmic reticulum is evolutionarily conserved

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