Structure and mechanism of an aspartimide-dependent peptide ligase in human legumain.
Structure and mechanism of an aspartimide-dependent peptide ligase in human legumain.
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人豆蛋白酶中依赖天冬氨酸的肽连接酶的结构和机制。
DOI：
10.1002/anie.201409135
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发表时间：
2015-03-02
期刊：
影响因子：
--
通讯作者：
Brandstetter H
中科院分区：
文献类型：
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作者：
Dall E;Fegg JC;Briza P;Brandstetter H
肽连接酶通过在ATP或NTP的能量驱动下合成新的肽键来扩展遗传编码的蛋白质结构的库。在这里，我们报告了在人类豆荚蛋白（AEP）中发现的真正的连接酶活性，其在免疫和肿瘤进展中具有重要作用，被认为是由于其已建立的半胱氨酸蛋白酶活性。无视教条，连接酶反应是独立的催化半胱氨酸，但利用内源性能源水库，从保守的天冬氨酸转换为亚稳态天冬酰胺的结果。Legumain的双重蛋白酶-连接酶活性是pH-，因此定位受控，分别在酸性和中性pH下占主导地位。它们的相关性包括半胱氨酸蛋白酶抑制剂和酶（in）激活的可逆开关，并可能影响三维MHC表位的产生。天冬氨酸-天冬酰亚胺（琥珀酰亚胺）对代表了ATP稀缺环境中耦合吸能反应的新范例。
Peptide ligases expand the repertoire of genetically encoded protein architectures by synthesizing new peptide bonds, energetically driven by ATP or NTPs. Here, we report the discovery of a genuine ligase activity in human legumain (AEP) which has important roles in immunity and tumor progression that were believed to be due to its established cysteine protease activity. Defying dogma, the ligase reaction is independent of the catalytic cysteine but exploits an endogenous energy reservoir that results from the conversion of a conserved aspartate to a metastable aspartimide. Legumain’s dual protease–ligase activities are pH- and thus localization controlled, dominating at acidic and neutral pH, respectively. Their relevance includes reversible on–off switching of cystatin inhibitors and enzyme (in)activation, and may affect the generation of three-dimensional MHC epitopes. The aspartate–aspartimide (succinimide) pair represents a new paradigm of coupling endergonic reactions in ATP-scarce environments.