Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α
Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY are novel substrates of fibroblast activation protein-α
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DOI：
10.1111/j.1742-4658.2011.08051.x
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发表时间：
2011-04-01
期刊：
影响因子：
5.4
通讯作者：
Gorrell, Mark D.
中科院分区：
文献类型：
--
作者：
Keane, Fiona M.;Nadvi, Naveed A.;Gorrell, Mark D.
成纤维细胞活化蛋白-α（FAP）是脯氨酰寡肽酶家族的细胞表面表达的可溶性酶，其包括二肽基肽酶4（DPP 4）。FAP通常不在正常成人组织中表达，但在纤维化中的活化肌成纤维细胞和肝星状细胞以及上皮肿瘤的基质成纤维细胞中以高水平被发现。FAP具有罕见的催化活性，水解脯氨酸后键的两个或多个残基的N-末端的目标底物。α（2）-抗纤溶酶是FAP内肽酶活性的重要生理底物。本研究报道了FAP二肽基肽酶活性的第一个天然底物。神经肽Y、B型利钠肽、P物质和肽YY是FAP最有效的水解底物，也是FAP最先被鉴定的激素底物。此外，FAP缓慢水解其他激素肽，如肠促胰岛素胰高血糖素样肽-1和葡萄糖依赖性促胰岛素肽，它们是有效的DPP 4底物。FAP显示可忽略或没有水解的八种趋化因子，这些趋化因子容易被DPP 4水解。FAP底物的这种新的鉴定通过指示在心脏功能和神经生物学中的潜在作用，进一步加深了我们对这种独特蛋白酶的理解。
Fibroblast activation protein-alpha (FAP) is a cell surface-expressed and soluble enzyme of the prolyl oligopeptidase family, which includes dipeptidyl peptidase 4 (DPP4). FAP is not generally expressed in normal adult tissues, but is found at high levels in activated myofibroblasts and hepatic stellate cells in fibrosis and in stromal fibroblasts of epithelial tumours. FAP possesses a rare catalytic activity, hydrolysis of the post-proline bond two or more residues from the N-terminus of target substrates. alpha(2)-antiplasmin is an important physiological substrate of FAP endopeptidase activity. This study reports the first natural substrates of FAP dipeptidyl peptidase activity. Neuropeptide Y, B-type natriuretic peptide, substance P and peptide YY were the most efficiently hydrolysed substrates and the first hormone substrates of FAP to be identified. In addition, FAP slowly hydrolysed other hormone peptides, such as the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are efficient DPP4 substrates. FAP showed negligible or no hydrolysis of eight chemokines that are readily hydrolysed by DPP4. This novel identification of FAP substrates furthers our understanding of this unique protease by indicating potential roles in cardiac function and neurobiology.