Nemoda Zsófia, Sahin-Tóth Miklós
Department of Molecular and Cell Biology, Boston University, Goldman School of Dental Medicine, Boston, Massachusetts 02118, USA.
J Biol Chem. 2006 Apr 28;281(17):11879-86. doi: 10.1074/jbc.M600124200. Epub 2006 Feb 27.
Trypsin-mediated trypsinogen activation (autoactivation) facilitates digestive zymogen activation in the duodenum but may precipitate pancreatitis if it occurs prematurely in the pancreas. Autoactivation of human cationic trypsinogen is inhibited by a repulsive electrostatic interaction between the unique Asp218 on the surface of cationic trypsin and the conserved tetra-aspartate (Asp19-22) motif in the trypsinogen activation peptide (Nemoda, Z., and Sahin-Tóth, 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 Phe18-Asp19 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 approximately 3-fold, and this effect is dependent on the presence of Asp218. 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.
胰蛋白酶介导的胰蛋白酶原激活（自身激活）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，则可能引发胰腺炎。人阳离子胰蛋白酶原的自身激活受到阳离子胰蛋白酶表面独特的天冬氨酸218与胰蛋白酶原激活肽中保守的四天冬氨酸（天冬氨酸19 - 22）基序之间排斥性静电相互作用的抑制（内莫达，Z.，和萨欣 - 托特，M.（2005年）《生物化学杂志》280卷，29645 - 29652页）。在此我们描述这种相互作用受糜蛋白酶C（钙激活蛋白酶）调节，糜蛋白酶C可特异性切割胰蛋白酶原激活肽中的苯丙氨酸18 - 天冬氨酸19肽键并去除N端三肽。相比之下，糜蛋白酶B、弹性蛋白酶2A或弹性蛋白酶3A（蛋白酶E）则无效。N端截短的阳离子胰蛋白酶原的自身激活被刺激约3倍，且这种效应依赖于天冬氨酸218的存在。由于糜蛋白酶原C被胰蛋白酶激活，且糜蛋白酶C刺激胰蛋白酶原激活，这些反应在人类消化酶级联反应中建立了正反馈机制。此外，胰腺中糜蛋白酶原C的不适当激活可能导致胰腺炎的发生。与此观点一致，阳离子胰蛋白酶原中与胰腺炎相关的A16V突变使激活肽的糜蛋白酶C介导的加工速率提高4倍，并在体外导致胰蛋白酶原激活加速。
