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Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity.

ABSTRACT: Sulfatide derived from the myelin stimulates a distinct population of CD1d-restricted natural killer T (NKT) cells. Cis-tetracosenoyl sulfatide is one of the immunodominant species in myelin as identified by proliferation, cytokine secretion, and CD1d tetramer staining. The crystal structure of mouse CD1d in complex with cis-tetracosenoyl sulfatide at 1.9 A resolution reveals that the longer cis-tetracosenoyl fatty acid chain fully occupies the A' pocket of the CD1d binding groove, whereas the sphingosine chain fills up the F' pocket. A precise hydrogen bond network in the center of the binding groove orients and positions the ceramide backbone for insertion of the lipid tails in their respective pockets. The 3'-sulfated galactose headgroup is highly exposed for presentation to the T cell receptor and projects up and away from the binding pocket due to its beta linkage, compared with the more intimate binding of the alpha-glactosyl ceramide headgroup to CD1d. These structure and binding data on sulfatide presentation by CD1d have important implications for the design of therapeutics that target T cells reactive for myelin glycolipids in autoimmune diseases of the central nervous system.

SUBMITTER: Zajonc DM

PROVIDER: S-EPMC2213337 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity.

Zajonc Dirk M DM Maricic Igor I Wu Douglass D Halder Ramesh R Roy Keshab K Wong Chi-Huey CH Kumar Vipin V Wilson Ian A IA

The Journal of experimental medicine 20051128 11

Sulfatide derived from the myelin stimulates a distinct population of CD1d-restricted natural killer T (NKT) cells. Cis-tetracosenoyl sulfatide is one of the immunodominant species in myelin as identified by proliferation, cytokine secretion, and CD1d tetramer staining. The crystal structure of mouse CD1d in complex with cis-tetracosenoyl sulfatide at 1.9 A resolution reveals that the longer cis-tetracosenoyl fatty acid chain fully occupies the A' pocket of the CD1d binding groove, whereas the s ...[more]

PMID: 16314439

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Project description:Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST(-/-) ) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities and progressive tremors starting at 4-6 weeks of age. Although these phenotypes suggest that sulfatide plays a critical role in myelin maintenance/function, the underlying mechanisms remain largely unknown. We analyzed the major CNS myelin proteins and the major lipids enriched in the myelin in a spatiotemporal manner. We found a one-third reduction of the major compact myelin proteins (myelin basic protein, myelin basic protein, and proteolipid protein, PLP) and an equivalent post-developmental loss of myelin lipids, providing the molecular basis behind the thinner myelin sheaths. Our lipidomics data demonstrated that the observed global reduction of myelin lipid content was not because of an increase of lipid degradation but rather to the reduction of their synthesis by oligodendrocytes. We also showed that sulfatide depletion leads to region-specific effects on non-compact myelin, dramatically affecting the paranode (neurofascin 155) and the major inner tongue myelin protein (myelin-associated glycoprotein). Moreover, we demonstrated that sulfatide promotes the interaction between adjacent PLP extracellular domains, evidenced by a progressive decline of high molecular weight PLP complexes in CST(-/-) mice, providing an explanation at a molecular level regarding the uncompacted myelin sheaths. Finally, we proposed that the dramatic losses of neurofascin 155 and PLP interactions are responsible for the progressive tremors and eventual ataxia. In summary, we unraveled novel molecular insights into the critical role of sulfatide in myelin maintenance/function. Cerebroside sulfotransferase (CST) catalyzes the production of sulfatide, a major class of myelin-specific lipids. CST knockout (CST(-/-) ) mice in which sulfatide is completely depleted are born healthy, but display myelin abnormalities We show in our study that sulfatide depletion leads to losses of myelin proteins and lipids, and impairment of myelin functions, unraveling novel molecular insights into the critical role of sulfatide in myelin maintenance/function.

Dataset Information

Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity.

Publications

Structural basis for CD1d presentation of a sulfatide derived from myelin and its implications for autoimmunity.

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