The Crystal Structure of the MAP Kinase LmaMPK10 from Leishmania Major Reveals Parasite-Specific Features and Regulatory Mechanisms
The Crystal Structure of the MAP Kinase LmaMPK10 from Leishmania Major Reveals Parasite-Specific Features and Regulatory Mechanisms
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DOI：
10.1016/j.str.2012.07.005
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发表时间：
2012-10-10
期刊：
影响因子：
5.7
通讯作者：
Buschiazzo, Alejandro
中科院分区：
文献类型：
--
作者：
Horjales, Sofia;Schmidt-Arras, Dirk;Buschiazzo, Alejandro
丝裂原活化蛋白激酶(MAPKs)参与环境信号传感。因此，它们有望在锥虫寄生虫的生物学中发挥关键作用，锥虫寄生虫表现出复杂的生活周期，并使用细胞外线索来调节细胞分化。尽管它们具有相关性，但缺乏锥虫MAPK的结构数据。我们现在已经确定了利什曼原虫LmaMPK10的晶体结构，LmaMPK10是一种阶段特异性激活的MAPK，无论是单独激活还是与SB203580结合。LmaMPK10与p38的同源性高于其他人类MAPK的同源性。然而，在催化口袋以及N-末端叶的潜在调控位点上可以识别出显著的差异。LmaMPK10中修改后的口袋结构排除了哺乳动物MAPK中观察到的DFG-In/DFG-Out调控翻转。还研究了LmaMPK10与核苷酸的相互作用，揭示了潜在的C端自抑制机制。总体而言，这些数据应该会加速发现干扰LmaMPK10功能的分子，与抗利什曼药物开发策略相关。
Mitogen-activated protein kinases (MAPKs) are involved in environmental signal sensing. They are thus expected to play key roles in the biology of Trypanosomatid parasites, which display complex life cycles and use extracellular cues to modulate cell differentiation. Despite their relevance, structural data of Trypanosomatid MAPKs is lacking. We have now determined the crystal structure of Leishmania major LmaMPK10, a stage-specifically activated MAPK, both alone and in complex with SB203580. LmaMPK10 was observed to be more similar to p38 than to other human MAPKs. However, significant differences could be identified in the catalytic pocket, as well as in potentially regulatory sites in the N-terminal lobe. The modified pocket architecture in LmaMPK10 precludes DFG-in/DFG-out regulatory flipping as observed in mammalian MAPKs. LmaMPK10-nucleotide association was also studied, revealing a potential C-terminal autoinhibitory mechanism. Overall, these data should speed the discovery of molecules interfering with LmaMPK10 functions, with relevance for antileishmanial drug development strategies.