The crystal structure of GXGD membrane protease FlaK.
The crystal structure of GXGD membrane protease FlaK.
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DOI：
10.1038/nature10218
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发表时间：
2011-07-17
期刊：
影响因子：
64.8
通讯作者：
Ha, Ya
中科院分区：
文献类型：
--
作者：
Hu, Jian;Xue, Yi;Lee, Sangwon;Ha, Ya
GXGD蛋白酶是多位膜蛋白，其对需要一对乙酰基残基的跨膜底物具有催化活性。该家族的代表性成员包括前鞭毛蛋白肽酶、4型前纤毛蛋白肽酶、早老素和信号肽肽酶。许多GXGD蛋白酶在医学中是重要的。例如，4型前菌毛蛋白肽酶可能有助于细菌的发病机制，早老素的突变与阿尔茨海默病有关。到目前为止，在这个蛋白酶家族中还没有原子分辨率结构。本文报道了海洋甲烷球菌前鞭毛蛋白肽酶FlaK的晶体结构。该结构包含六个跨膜螺旋。GXGD基序和一个短的跨膜螺旋，螺旋4，位于中心，被其他跨膜螺旋包围。晶体结构表明，蛋白酶必须经历构象变化，使GXGD基序和第二个必需的跨膜螺旋1的乙酰基残基紧密接近催化。来自生化分析的早老素模型的晶体结构的比较揭示了三个共同的跨膜段，类似地安排在活性位点周围。这一观察结果强化了原核生物和人类蛋白酶在进化上相关的观点。这里提出的晶体结构提供了一个框架，了解机制的GXGD蛋白酶，并可能有助于合理设计的抑制剂，针对特定的家庭成员。
The GXGD proteases are polytopic membrane proteins with catalytic activities against membrane-spanning substrates that require a pair of aspartyl residues. Representative members of the family include preflagellin peptidase, type 4 prepilin peptidase, presenilin and signal peptide peptidase. Many GXGD proteases are important in medicine. For example, type 4 prepilin peptidase may contribute to bacterial pathogenesis, and mutations in presenilin are associated with Alzheimer's disease. As yet, there is no atomic-resolution structure in this protease family. Here we report the crystal structure of FlaK, a preflagellin peptidase from Methanococcus maripaludis, solved at 3.6Å resolution. The structure contains six transmembrane helices. The GXGD motif and a short transmembrane helix, helix 4, are positioned at the centre, surrounded by other transmembrane helices. The crystal structure indicates that the protease must undergo conformational changes to bring the GXGD motif and a second essential aspartyl residue from transmembrane helix 1 into close proximity for catalysis. A comparison of the crystal structure with models of presenilin derived from biochemical analysis reveals three common transmembrane segments that are similarly arranged around the active site. This observation reinforces the idea that the prokaryotic and human proteases are evolutionarily related. The crystal structure presented here provides a framework for understanding the mechanism of the GXGD proteases, and may facilitate the rational design of inhibitors that target specific members of the family.
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影响因子：
4.8
作者：
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通讯作者：
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影响因子：
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DOI：
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发表时间：
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期刊：
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