Structural basis for Ca2+-induced activation of human PAD4
Structural basis for Ca2+-induced activation of human PAD4
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DOI：
10.1038/nsmb799
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发表时间：
2004-08-01
影响因子：
16.8
通讯作者：
Sato, M
中科院分区：
文献类型：
--
作者：
Arita, K;Hashimoto, H;Sato, M
肽基精氨酸脱亚胺酶4（PAD 4）是一种Ca 2+依赖性酶，催化蛋白质精氨酸残基转化为瓜氨酸。其基因是类风湿性关节炎的易感基因。在这里，我们提出了无钙野生型PAD 4的晶体结构，这表明多肽链采用了延长的折叠，其中N-末端结构域形成两个免疫球蛋白样亚结构域，C-末端结构域形成α/β螺旋桨结构。五个Ca 2+结合位点，其中没有一个采用EF-手基序，被确定在一个Ca 2+结合的无活性突变体的结构与和不结合底物。这些结构数据表明，Ca 2+结合诱导构象变化，产生活性位点裂缝。我们的研究结果确定了一种新的机制，酶激活钙离子，并了解蛋白质瓜氨酸的机制和开发PAD抑制药物治疗类风湿性关节炎是很重要的。
Peptidylarginine deiminase 4 (PAD4) is a Ca2+-dependent enzyme that catalyzes the conversion of protein arginine residues to citrulline. Its gene is a susceptibility locus for rheumatoid arthritis. Here we present the crystal structure of Ca2+-free wild-type PAD4, which shows that the polypeptide chain adopts an elongated fold in which the N-terminal domain forms two immunoglobulin-like subdomains, and the C-terminal domain forms an alpha/beta propeller structure. Five Ca2+-binding sites, none of which adopt an EF-hand motif, were identified in the structure of a Ca2+-bound inactive mutant with and without bound substrate. These structural data indicate that Ca2+ binding induces conformational changes that generate the active site cleft. Our findings identify a novel mechanism for enzyme activation by Ca2+ ions, and are important for understanding the mechanism of protein citrullination and for developing PAD-inhibiting drugs for the treatment of rheumatoid arthritis.