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小鼠微小病毒识别的唾液酸结构鉴定及结合亲和力在毒力适应中的作用。

Identification of the sialic acid structures recognized by minute virus of mice and the role of binding affinity in virulence adaptation.

作者信息

Nam Hyun-Joo, Gurda-Whitaker Brittney, Gan Wand Yee, Ilaria Shawen, McKenna Robert, Mehta Padmaja, Alvarez Richard A, Agbandje-McKenna Mavis

机构信息

Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida 32610, USA.

出版信息

J Biol Chem. 2006 Sep 1;281(35):25670-7. doi: 10.1074/jbc.M604421200. Epub 2006 Jul 5.

Abstract

Sialic acid binding is required for infectious cell surface receptor recognition by parvovirus minute virus of mice (MVM). We have utilized a glycan array consisting of approximately 180 different carbohydrate structures to identify the specific sialosides recognized by the prototype (MVMp) and immunosuppressive (MVMi) strains of MVM plus three virulent mutants of MVMp, MVMp-I362S, MVMp-K368R, and MVMp-I362S/K368R. All of the MVM capsids specifically bound to three structures with a terminal sialic acid-linked alpha2-3 to a common Galbeta1-4GlcNAc motif: Neu5Acalpha2-3Galbeta1-4GlcNAcbeta1-4Galbeta1-4GlcNAc (3'SiaLN-LN), Neu5Acalpha2-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4GlcNAcbeta1-3Galbeta1-4GlcNAc (3'SiaLN-LN-LN), and Neu5Acalpha2-3Galbeta1-4(Fucalpha1-3)-GlcNAcbeta1-3Galbeta1-4(Fucalpha1-3)GlcNAcbeta1-3Galbeta1-4(Fucalpha1-3)GlcNAc (sLe(x)-Le(x)-Le(x)). In addition, MVMi also recognized four multisialylated glycans with terminal alpha2-8 linkages: Neu5Acalpha2-8Neu5Acalpha2-8Neu5Acalpha ((Sia)(3)), Neu5Acalpha2-8Neu5Acalpha2-3Galbeta1-4Glc (GD3), Neu5Acalpha2-8Neu5Acalpha2-8Neu5Acalpha2-3Galbeta1-4Glc (GT3), and Neu5Acalpha2-8Neu5Acalpha2-3(GalNAcbeta1-4)Galbeta1-4Glc (GD2). Interestingly, the virulent MVMp-K368R mutant also recognized GT3. Analysis of the relative binding affinities using a surface plasmon resonance biospecific interaction (BIAcore) assay showed the wild-type MVMp and MVMi capsids binding with higher affinity to selected glycans compared with the virulent MVMp mutants. The reduced affinity of the virulent MVMp mutants are consistent with previous in vitro cell binding assays that had shown weaker binding to permissive cells compared with wild-type MVMp. This study identifies the sialic acid structures recognized by MVM. It also provides rationale for the tropism of MVM for malignant transformed cells that contain sLe(x) motifs and the neurotropism of MVMi, which is likely mediated via interactions with multisialylated glycans known to be tumor cell markers. Finally, the observations further implicate a decreased binding affinity for sialic acid in the in vivo adaptation of MVMp to a virulent phenotype.

摘要

小鼠细小病毒(MVM)感染性细胞表面受体识别需要唾液酸结合。我们利用了一个由大约180种不同碳水化合物结构组成的聚糖阵列,来鉴定MVM的原型株(MVMp)和免疫抑制株(MVMi)以及MVMp的三个强毒株突变体MVMp - I362S、MVMp - K368R和MVMp - I362S/K368R所识别的特定唾液酸苷。所有MVM衣壳均特异性结合到三种具有末端唾液酸连接的α2 - 3至共同的Galβ1 - 4GlcNAc基序的结构:Neu5Acα2 - 3Galβ1 - 4GlcNAcβ1 - 4Galβ1 - 4GlcNAc(3'SiaLN - LN)、Neu5Acα2 - 3Galβ1 - 4GlcNAcβ1 - 3Galβ1 - 4GlcNAcβ1 - 3Galβ1 - 4GlcNAc(3'SiaLN - LN - LN)以及Neu5Acα2 - 3Galβ1 - 4(Fucα1 - 3)- GlcNAcβ1 - 3Galβ1 - 4(Fucα1 - 3)GlcNAcβ1 - 3Galβ1 - 4(Fucα1 - 3)GlcNAc(sLe(x)-Le(x)-Le(x))。此外,MVMi还识别四种具有末端α2 - 8连接的多唾液酸化聚糖:Neu5Acα2 - 8Neu5Acα2 - 8Neu5Acα((Sia)(3))、Neu5Acα2 - 8Neu5Acα2 - 3Galβ1 - 4Glc(GD3)、Neu5Acα2 - 8Neu5Acα2 - 8Neu5Acα2 - 3Galβ1 - 4Glc(GT3)以及Neu5Acα2 - 8Neu5Acα2 - 3(GalNAcβ1 - 4)Galβ1 - 4Glc(GD2)。有趣的是,强毒株MVMp - K368R突变体也识别GT3。使用表面等离子体共振生物特异性相互作用(BIAcore)测定法分析相对结合亲和力表明,与强毒株MVMp突变体相比,野生型MVMp和MVMi衣壳与选定聚糖的结合亲和力更高。强毒株MVMp突变体亲和力的降低与先前的体外细胞结合试验一致,该试验表明与野生型MVMp相比,其与允许性细胞的结合较弱。本研究鉴定了MVM所识别的唾液酸结构。它还为MVM对含有sLe(x)基序的恶性转化细胞的嗜性以及MVMi的嗜神经性提供了理论依据,MVMi的嗜神经性可能是通过与已知为肿瘤细胞标志物的多唾液酸化聚糖相互作用介导的。最后,这些观察结果进一步表明MVMp在体内适应强毒表型过程中对唾液酸的结合亲和力降低。

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