Biophysical analysis of sialic acid recognition by the complement regulator Factor H.
Biophysical analysis of sialic acid recognition by the complement regulator Factor H.
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DOI：
10.1093/glycob/cwy061
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发表时间：
2018-10-01
期刊：
影响因子：
4.3
通讯作者：
Blaum BS
中科院分区：
文献类型：
--
作者：
Schmidt CQ;Hipgrave Ederveen AL;Harder MJ;Wuhrer M;Stehle T;Blaum BS
补体因子H（FH）是一种延长的和基本糖基化的20-结构域蛋白，是补体旁路途径（AP）的可溶性调节剂。它含有几个聚糖结合位点，介导α2-3连接唾液酸（FH结构域20）和糖胺聚糖（结构域6-8和19-20）的识别。FH还结合补体C3激活产物C3 b，这是一种强大的调理素，也是AP反馈环C3转化酶形成的焦点。在自由循环的FH中，结构域19-20中的C3 b结合位点被封闭，这是一种尚未完全理解的现象，可能是由FH的固有唾液酸化糖基化与其自身唾液酸结合位点之间的分子内相互作用介导的。为了评估这种可能性，我们表征了FH的唾液酸化相对于糖苷键类型，并寻找进一步的潜在的，尚未表征的唾液酸结合位点在FH和它的七域跨越剪接变体和同胞补体调节因子FH样-1（FHL-1）。我们还探测了FH与唾液酸变体Neu 5Gc的结合，Neu 5Gc在人类中不表达，但在限制人类AP的异源红细胞和FH转基因小鼠中表达。我们发现FH主要含有α2-6-连接的唾液酸，使得与其α2-3-唾液酸特异性结合位点的分子内相互作用和相关的自锁机制不太可能，证实FH中只有一个唾液酸结合位点而FHL-1中没有，并证明FH与非人唾液酸Neu 5Gc直接结合，支持FH转基因小鼠模型用于补体相关疾病的研究。
Complement factor H (FH), an elongated and substantially glycosylated 20-domain protein, is a soluble regulator of the complement alternative pathway (AP). It contains several glycan binding sites which mediate recognition of α2-3-linked sialic acid (FH domain 20) and glycosaminoglycans (domains 6–8 and 19–20). FH also binds the complement C3-activation product C3b, a powerful opsonin and focal point for the formation of C3-convertases of the AP feedback loop. In freely circulating FH the C3b binding site in domains 19–20 is occluded, a phenomenon that is not fully understood and could be mediated by an intramolecular interaction between FH’s intrinsic sialylated glycosylation and its own sialic acid binding site. In order to assess this possibility, we characterized FH’s sialylation with respect to glycosidic linkage type and searched for further potential, not yet characterized sialic acid binding sites in FH and its seven-domain spanning splice variant and fellow complement regulator FH like-1 (FHL-1). We also probed FH binding to the sialic acid variant Neu5Gc which is not expressed in humans but on heterologous erythrocytes that restrict the human AP and in FH transgenic mice. We find that FH contains mostly α2-6-linked sialic acid, making an intramolecular interaction with its α2-3-sialic acid specific binding site and an associated self-lock mechanism unlikely, substantiate that there is only a single sialic acid binding site in FH and none in FHL-1, and demonstrate direct binding of FH to the nonhuman sialic acid Neu5Gc, supporting the use of FH transgenic mouse models for studies of complement-related diseases.
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影响因子：
7.3
作者：
Langford-Smith A;Day AJ;Bishop PN;Clark SJ
通讯作者：
Clark SJ
DOI：
10.4049/jimmunol.0804031
发表时间：
2009-06-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Ferreira VP;Herbert AP;Cortés C;McKee KA;Blaum BS;Esswein ST;Uhrín D;Barlow PN;Pangburn MK;Kavanagh D
通讯作者：
Kavanagh D
影响因子：
4.4
作者：
Ferreira, Viviana P.;Herbert, Andrew P.;Pangburn, Michael K.
通讯作者：
Pangburn, Michael K.
DOI：
10.4049/jimmunol.1401613
发表时间：
2014-11-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Clark SJ;Schmidt CQ;White AM;Hakobyan S;Morgan BP;Bishop PN
通讯作者：
Bishop PN
DOI：
10.1073/pnas.1017087108
发表时间：
2011-02-15
影响因子：
11.1
作者：
Kajander, Tommi;Lehtinen, Markus J.;Jokiranta, T. Sakari
通讯作者：
Jokiranta, T. Sakari