Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen
Chymotrypsin C (caldecrin) stimulates autoactivation of human cationic trypsinogen
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DOI：
10.1074/jbc.m600124200
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发表时间：
2006-04-28
影响因子：
4.8
通讯作者：
Sahin-Tóth, M
中科院分区：
文献类型：
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作者：
Nemoda, Z;Sahin-Tóth, M
胰蛋白酶介导的胰蛋白酶原激活（自激活）促进十二指肠中消化酶原的激活，但如果在胰腺中过早发生，则可能导致胰腺炎。人阳离子胰蛋白酶原的自激活被阳离子胰蛋白酶表面上独特的Asp（218）和胰蛋白酶原激活肽中保守的四天冬氨酸（Asp（19-22））基序之间的排斥静电相互作用抑制（Nemoda，Z.，和Sahin-Toth，M.（2005）J.Biol.Chem.280，29645-29652）。在这里，我们描述了这种相互作用是由胰凝乳蛋白酶C（钙调蛋白），它可以特异性地切割胰蛋白酶原激活肽中的Phe（18）-Asp（19）肽键，并删除N-末端三肽调节。相反，糜蛋白酶B、弹性蛋白酶2A或弹性蛋白酶3A（蛋白酶E）是无效的。N-末端截短的阳离子胰蛋白酶原的自激活被刺激了3倍，这种作用依赖于Asp的存在（218）。由于胰凝乳蛋白酶原C被胰蛋白酶激活，而胰凝乳蛋白酶C刺激胰蛋白酶原激活，这些反应在人类的消化酶级联中建立了正反馈机制。此外，胰凝乳蛋白酶原C在胰腺中的不适当激活可能有助于胰腺炎的发展。与此观点一致，胰腺炎相关的突变A16 V在阳离子胰蛋白酶原增加速率胰凝乳蛋白酶C介导的处理的激活肽4倍，并导致加速胰蛋白酶原激活体外。
Trypsin-mediated trypsinogen activation (autoactivation) facilitates digestive zymogen activation in the duodenum but may precipitate pancreatitis if it occurs prematurely in the pancreas. Auto-activation of human cationic trypsinogen is inhibited by a repulsive electrostatic interaction between the unique Asp(218) on the surface of cationic trypsin and the conserved tetra-aspartate (Asp(19-22)) motif in the trypsinogen activation peptide (Nemoda, Z., and Sahin-Toth, M. (2005) J. Biol. Chem. 280, 29645-29652). Here we describe that this interaction is regulated by chymotrypsin C (caldecrin), which can specifically cleave the Phe(18)-Asp(19) peptide bond in the trypsinogen activation peptide and remove the N-terminal tripeptide. In contrast, chymotrypsin B, elastase 2A, or elastase 3A (proteinase E) are ineffective. Autoactivation of N-terminally truncated cationic trypsinogen is stimulated similar to 3-fold, and this effect is dependent on the presence of Asp(218). Because chymotrypsinogen C is activated by trypsin, and chymotrypsin C stimulates trypsinogen activation, these reactions establish a positive feedback mechanism in the digestive enzyme cascade of humans. Furthermore, inappropriate activation of chymotrypsinogen C in the pancreas may contribute to the development of pancreatitis. Consistent with this notion, the pancreatitis-associated mutation A16V in cationic trypsinogen increases the rate of chymotrypsin C-mediated processing of the activation peptide 4-fold and causes accelerated trypsinogen activation in vitro.