Streptokinase variants from Streptococcus pyogenes isolates display altered plasminogen activation characteristics - implications for pathogenesis
Streptokinase variants from Streptococcus pyogenes isolates display altered plasminogen activation characteristics - implications for pathogenesis
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DOI：
10.1111/mmi.12037
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发表时间：
2012-12-01
影响因子：
3.6
通讯作者：
McArthur, Jason D.
中科院分区：
文献类型：
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作者：
Cook, Simon M.;Skora, Amanda;McArthur, Jason D.
化脓性链球菌（A组链球菌，GAS）分泌链激酶，一种有效的纤溶酶原激活蛋白。在GAS分离株中，链激酶基因序列（ska）具有多态性，可分为两个不同的序列簇（称为簇1和簇2），而簇2又可进一步分为子簇2a和2b。在本研究中，远紫外圆二色光谱显示纯化的每种类型的链激酶变体具有相似的二级结构。2b型链激酶变体不能通过非蛋白水解机制在葡纤溶酶原中产生活性位点，而其他所有变体都具有这种能力。此外，与其他链激酶变体相比，2b型变体对葡萄糖-纤溶酶原的亲和力降低了29- 35倍。当激活物复合物与纤溶酶结合时，所有SK变异都能激活葡萄糖-纤溶酶原；而2b型和1型复合物被a2-抗纤溶酶抑制。在侵袭性疾病小鼠模型中，将M1T1 GAS菌株5448中的skattype -2a与skattype -2b交换会导致毒力降低，而将skattype -2a与skattype -1交换到5448中会导致毒力增加。这些发现表明，GAS分离株产生的链激酶变体利用不同的纤溶酶原激活途径，这直接影响了该生物体的发病机制。
Streptococcus pyogenes (group A streptococcus, GAS) secretes streptokinase, a potent plasminogen activating protein. Among GAS isolates, streptokinase gene sequences (ska) are polymorphic and can be grouped into two distinct sequence clusters (termed cluster type-1 and cluster type-2) with cluster type-2 being further divided into sub-clusters type-2a and type-2b. In this study, far-UV circular dichroism spectroscopy indicated that purified streptokinase variants of each type displayed similar secondary structure. Type-2b streptokinase variants could not generate an active site in Glu-plasminogen through non-proteolytic mechanisms while all other variants had this capability. Furthermore, when compared with other streptokinase variants, type-2b variants displayed a 29- to 35-fold reduction in affinity for Glu-plasminogen. All SK variants could activate Glu-plasminogen when an activator complex was preformed with plasmin; however, type-2b and type-1 complexes were inhibited by a2-antiplasmin. Exchanging skatype-2a in the M1T1 GAS strain 5448 with skatype-2b caused a reduction in virulence while exchanging skatype-2a with skatype-1 into 5448 produced an increase in virulence when using a mouse model of invasive disease. These findings suggest that streptokinase variants produced by GAS isolates utilize distinct plasminogen activation pathways, which directly affects the pathogenesis of this organism.