Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune disease.
Defects in DNA degradation revealed in crystal structures of TREX1 exonuclease mutations linked to autoimmune disease.
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DOI：
10.1016/j.dnarep.2011.10.007
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发表时间：
2012-01-02
期刊：
影响因子：
3.8
通讯作者：
Hollis, Thomas
中科院分区：
文献类型：
--
作者：
Bailey, Suzanna L.;Harvey, Scott;Perrino, Fred W.;Hollis, Thomas
人类TREX1 3‘外切酶的突变与艾卡迪-古蒂埃综合征(AGS)和家族性冻疮狼疮(FCL)有关。AGS和FCL都是自身免疫性疾病，会导致干扰素α水平和循环中的DNA抗体水平增加。TREX1是内质网(ER)相关SET复合体的成员，参与颗粒酶A介导的细胞死亡以降解镍基因组DNA。TREX1活性的丧失可能导致双链DNA(DsDNA)降解中间产物的积累，从而触发自身免疫激活。对来自AGS和FCL患者的TREX1wt载脂蛋白、显性D200H、D200N和D18N同源二聚体突变体以及隐性V201D同源二聚体突变体的X射线晶体结构进行了测定。D200H和D200N突变蛋白的结构表明，酶失去了活性中心金属的配位，催化组氨酸(H195)被捕获在远离活性中心的构象中。TREX1 D18N和V201D突变体能够与活性中心的两种金属结合，但金属间的距离大于催化的最佳距离。此外，所有的突变结构都显示出催化组氨酸的流动性降低，这为催化活性的丧失提供了进一步的解释。突变的TREX1蛋白的结构提供了与人类疾病相关的功能障碍的洞察力。此外，TREX1脱辅基蛋白结构与先前确定的野生型底物和产物结构一起使我们能够提出TREX1核酸外切酶的不同机制。
Mutations within the human TREX1 3' exonuclease are associated with Aicardi-Goutières Syndrome (AGS) and familial chilblain lupus (FCL). Both AGS and FCL are autoimmune diseases that result in increased levels of interferon alpha and circulating antibodies to DNA. TREX1 is a member of the endoplasmic reticulum (ER)-associated SET complex and participates in granzyme A-mediated cell death to degrade nicked genomic DNA. The loss of TREX1 activity may result in the accumulation of double-stranded DNA (dsDNA) degradation intermediates that trigger autoimmune activation. The X-ray crystal structures of the TREX1 wt apoprotein, the dominant D200H, D200N and D18N homodimer mutants derived from AGS and FCL patients, as well as the recessive V201D homodimer mutant have been determined. The structures of the D200H and D200N mutant proteins reveal the enzyme has lost coordination of one of the active site metals, and the catalytic histidine (H195) is trapped in a conformation pointing away from the active site. The TREX1 D18N and V201D mutants are able to bind both metals in the active site, but with inter-metal distances that are larger than optimal for catalysis. Additionally, all of the mutant structures reveal a reduced mobility in the catalytic histidine, providing further explanation for the loss of catalytic activity. The structures of the mutant TREX1 proteins provide insight into the dysfunction relating to human disease. Additionally, the TREX1 apoprotein structure together with the previously determined wild type substrate and product structures allow us to propose a distinct mechanism for the TREX1 exonuclease.
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影响因子：
15
作者：
Cisneros GA;Perera L;Schaaper RM;Pedersen LC;London RE;Pedersen LG;Darden TA
通讯作者：
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DOI：
10.1107/s0907444904019158
发表时间：
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作者：
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