Crystal structure of the apoptosis-inducing human granzyme A dimer
Crystal structure of the apoptosis-inducing human granzyme A dimer
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DOI：
10.1038/nsb945
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发表时间：
2003-07-01
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影响因子：
--
通讯作者：
Jenne, DE
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作者：
Hink-Schauer, C;Estébanez-Perpiná, E;Jenne, DE
颗粒酶A（GzmA）属于胰蛋白酶样丝氨酸蛋白酶家族，定位于活化的淋巴细胞和自然杀伤（NK）细胞的细胞质颗粒中。与相关的颗粒酶B（Gzm B）相比，GzmA形成稳定的二硫键连接的同源二聚体，并以不依赖半胱天冬酶的方式触发靶细胞死亡。GzmA对含有SET（也称为推定的HLA相关蛋白II或PHAPII）、PHAPI（pp 32，富含亮氨酸的酸性核蛋白）和HMG 2的高分子量复合物的有限蛋白水解释放出NM 23-H1，这是一种导致核DNA单链断裂的Mg 2+依赖性DNA酶。通过在2.5埃的分辨率下分析二聚体GzmA结构，我们确定了作为独特的功能串联排列的两个结构域的底物结合约束和选择性优势。两个亚基的活性位点指向相反的方向，附近的非催化表面可以作为外位点，以类似于葡激酶或链激酶的方式将底物呈递给相邻伴侣的活性位点区域，所述葡激酶或链激酶将纤溶酶原呈递给辅因子纤溶酶和辅因子纤溶酶原复合物。
Granzyme A (GzmA) belongs to a family of trypsin-like serine proteases localized in cytoplasmic granules of activated lymphocytes and natural killer (NK) cells. In contrast to the related granzyme B (GzmB), GzmA forms a stable disulfide-linked homodimer and triggers target-cell death in a caspase-independent way. Limited proteolysis of a high-molecular-mass complex containing SET (also named putative HLA-associated protein II or PHAPII), PHAPI (pp32, leucine-rich acidic nuclear protein) and HMG2 by GzmA liberates NM23-H1, a Mg2+-dependent DNase that causes single-stranded breaks in nuclear DNA. By analyzing the dimeric GzmA structure at a resolution of 2.5 Angstrom, we determined the substrate-binding constraints and selective advantages of the two domains arranged as a unique functional tandem. The active sites of the two subunits point in opposite directions and the nearby noncatalytic surfaces can function as exosites, presenting substrates to the active site region of the adjacent partner in a manner analogous to staphylokinase or streptokinase, which present plasminogen to the cofactor plasmin and cofactor plasminogen complexes.