Crystal Structure of the N-Terminal Domain of Sialoadhesin in Complex with 3′ Sialyllactose at 1.85 Å Resolution

May, Andrew P.; Robinson, Robert; Vinson, Mary; Crocker, Paul R.; Jones, E Y

doi:10.1016/s1097-2765(00)80071-4

Cited by 269 publications

(301 citation statements)

References 56 publications

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“…25): (i) the N-terminal region leading to the ␤-strand A; (ii) loop C-CЈ; (iii) loop CЈ-D; and (iv) the ␤-strand F, which harbors the essential arginine. Of these, regions i, ii, and iv may be relevant to glycan recognition, as suggested by previous in vitro mutagenesis studies (25,29,30). This result suggests that rapid evolution of the Ig1 of CD33rSiglecs may be related to the modification of these molecules to accommodate ongoing changes in host sialylation patterns.…”

Section: Rapid Accumulation Of Nonsynonymous Substitutions In the Firstsupporting

confidence: 52%

Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms

Angata

Margulies

Green

et al. 2004

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

153

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Siglecs are a recently discovered family of animal lectins that belong to the Ig superfamily and recognize sialic acids (Sias). CD33-related Siglecs (CD33rSiglecs) are a subgroup with as-yetunknown functions, characterized by sequence homology, expression on innate immune cells, conserved cytosolic tyrosine-based signaling motifs, and a clustered localization of their genes. To better understand the biology and evolution of CD33rSiglecs, we sequenced and compared the CD33rSiglec gene cluster from multiple mammalian species. Within the sequenced region, the segments containing CD33rSiglec genes showed a lower degree of sequence conservation. In contrast to the adjacent conserved kallikrein-like genes, the CD33rSiglec genes showed extensive species differences, including expansions of gene subsets; gene deletions, including one human-specific loss of a novel functional primate Siglec (Siglec-13); exon shuffling, generating hybrid genes; accelerated accumulation of nonsynonymous substitutions in the Sia-recognition domain; and multiple instances of mutations of an arginine residue essential for Sia recognition in otherwise intact Siglecs. Nonsynonymous differences between human and chimpanzee orthologs showed uneven distribution between the two ␤ sheets of the Sia-recognition domain, suggesting biased mutation accumulation. These data indicate that CD33rSiglec genes are undergoing rapid evolution via multiple genetic mechanisms, possibly due to an evolutionary ''arms race'' between hosts and pathogens involving Sia recognition. These studies, which reflect one of the most complete comparative sequence analyses of a rapidly evolving gene cluster, provide a clearer picture of the ortholog status of CD33rSiglecs among primates and rodents and also facilitate rational recommendations regarding their nomenclature.

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Section: Rapid Accumulation Of Nonsynonymous Substitutions In the Firstsupporting

confidence: 52%

Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms

Angata

Margulies

Green

et al. 2004

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

153

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“…These results suggest that there may be two independent sites for binding sialic acid on MAG as suggested previously by others (26,64,65) from analysis of MAG binding to ganglioside ligands. This conclusion was also reached by Vinson and co-workers (22,60,66) who mutated the conserved Arg-118 essential for sialic acid binding in sialoadhesin and found that MAG still mediated sialic aciddependent effects on neurite outgrowth (67).…”

Section: Potent Inhibition Of Mag (Siglec-4) By O-linked Sialosides-tomentioning

confidence: 55%

“…More approachable has been the analysis of the specificity of siglecs to the sialoside sequence itself. The crystal structure for the sialoadhesin V-set domain with bound 3Ј-sialyllactose (NeuAc␣(2-3)Gal␤(1-4)Glc) revealed that sialoside binding is stabilized predominantly by contacts with the sialic acid, including a salt bridge between the C-2 carboxyl group and a highly conserved Arg at residue 97 (22). Yet numerous reports have documented that the siglecs differ in their specificity toward other elements of sialoside sequences (2,3).…”

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confidence: 99%

Sialoside Specificity of the Siglec Family Assessed Using Novel Multivalent Probes

Blixt¹,

Collins²,

Nieuwenhof³

et al. 2003

Journal of Biological Chemistry

213

111

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Ten of the 11 known human siglecs or their murine orthologs have been evaluated for their specificity for over 25 synthetic sialosides representing most of the major sequences terminating carbohydrate groups of glycoproteins and glycolipids. Analysis has been performed using a novel multivalent platform comprising biotinylated sialosides bound to a streptavidin-alkaline phosphatase conjugate. Each siglec was found to have a unique specificity for binding 16 different sialoside-streptavidin-alkaline phosphatase probes. The relative affinities of monovalent sialosides were assessed for each siglec in competitive inhibition studies. The quantitative data obtained allows a detailed analysis of each siglec for the relative importance of sialic acid and the penultimate oligosaccharide sequence on binding affinity and specificity. Most remarkable was the finding that myelin-associated glycoprotein (Siglec-4) binds with 500 -10,000-fold higher affinity to a series of mono-and di-sialylated derivatives of the O-linked T-antigen (Gal␤(1-3)-GalNAc␣OThr) as compared with ␣-methyl-NeuAc.

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“…MOG is structurally similar to other IgV domains such as the peripheral nerve system protein P zero (27), the IgV domains of the ␥␦-T cell receptor (28), and various variable antibody domains. The nearest structural neighbors of MOG are the N-terminal domains of the costimulatory molecule B7-2 (29) (CD86) and sialoadhesin (30), which superimpose with MOG with rms deviations of 1.18 and 1.37 Å for 97 and 100 aligned C ␣ atoms, respectively.…”

Section: Resultsmentioning

confidence: 99%

Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

Breithaupt

Schubart

Zander

et al. 2003

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

123

120

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M ultiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) associated with autoaggressive T and B cell responses to various myelin proteins. Myelin oligodendrocyte glycoprotein (MOG) was identified as a candidate autoantigen in MS because it induces a demyelinating antibody response in laboratory animals with experimental autoimmune encephalomyelitis (EAE), an animal model of MS (1). MOG is a quantitatively minor type I transmembrane CNS protein of unknown function with a single extracellular Ig-like domain (2). In contrast to other CNS proteins, MOG is found only in mammals and is highly conserved across species. It is expressed exclusively in the CNS by myelin-forming oligodendrocytes and is preferentially localized at the outermost surface of the myelin sheath thus directly exposed to autoantibodies in the extracellular milieu. MOG is the only antigen that can induce both a pathogenic demyelinating autoantibody response and an encephalitogenic T cell response in experimental animals (3). In MOG-induced EAE this combination of immune effector mechanisms reproduces the demyelinating pathology seen in the majority of patients with MS. The clinical relevance of autoimmune responses to MOG in MS is supported by reports that MS is associated with enhanced MOG-specific T and B cell responses and by the identification of MOG-specific antibodies associated with myelin debris in actively demyelinating MS lesions (4). Experimental evidence indicates that the autoantibody response to MOG is heterogeneous; demyelinating MOG-specific autoantibodies recognize purely conformation-dependent epitopes whereas MOG peptide-specific antibodies fail to recognize the native protein (5-7). To examine the structural basis of the pathogenic autoantibody response to MOG we determined the crystal structures of the extracellular domain of rat MOG (residues 1-126, MOG Igd ) and a complex of MOG Igd with the chimeric antigen-binding fragment (Fab) of the demyelinating MOG-specific monoclonal antibody 8-18C5 (8). Materials and Methods Preparation of Recombinant MOG Igd and the MOG Igd -(8-18C5)-FabComplex. The cDNA of the extracellular domain of rat MOG (residues 1-125) was subcloned into the His-tag expression vector pQE-12. The protein was overexpressed in inclusion bodies in Escherichia coli, refolded, and further purified by nickel-nitrilotriacetic acid affinity chromatography and gel filtration. Selenomethionine (SeMet)-labeled protein was produced in the methionine-auxotrophic E. coli strain B834(DE3) and grown in minimal medium with SeMet (0.3 mM) substituted for methionine. The cDNA of the variable domains of the mouse monoclonal antibody 8-18C5 was subcloned into the expression vector pASK107, yielding the chimeric (8-18C5)-Fab composed of the 8-18C5 variable domains, the human IgG constant domains, and the Strep tag II fused to the C terminus of the heavy chain (9, 10). (8-18C5)-Fab was produced by periplasmic secretion in E. coli and purified by streptavidin affinity chromatogr...

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Crystal Structure of the N-Terminal Domain of Sialoadhesin in Complex with 3′ Sialyllactose at 1.85 Å Resolution

Cited by 269 publications

References 56 publications

Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms

Large-scale sequencing of the CD33-related Siglec gene cluster in five mammalian species reveals rapid evolution by multiple mechanisms

Sialoside Specificity of the Siglec Family Assessed Using Novel Multivalent Probes

Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein

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