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Activity of human kallikrein-related peptidase 6 (KLK6) on substrates containing sequences of basic amino acids. Is it a processing protease?

机译:人激肽释放酶相关肽酶6(KLK6)在含有碱性氨基酸序列的底物上的活性。它是加工蛋白酶吗?

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摘要

Human kallikrein 6 (KLK6) is highly expressed in the central nervous system and with elevated level in demyelinating disease. KLK6 has a very restricted specificity for arginine (R) and hydrolyses myelin basic protein, protein activator receptors and human ionotropic glutamate receptor subunits. Here we report a previously unreported activity of KLK6 on peptides containing clusters of basic amino acids, as in synthetic fluorogenic peptidyl-Arg-7-amino-4-carbamoylmethylcoumarin (peptidyl-ACC) peptides and FRET peptides in the format of Abz-peptidyl-Q-EDDnp (where Abz=ortho-aminobenzoic acid and Q-EDDnp=glutaminyl-N-(2,4-dinitrophenyl) ethylenediamine), in which pairs or sequences of basic amino acids (R or K) were introduced. Surprisingly, KLK6 hydrolyzed the fluorogenic peptides Bz-A-R(↓)R-ACC and Z-R(↓)R-MCA between the two R groups, resulting in non-fluorescent products. FRET peptides containing furin processing sequences of human MMP-14, nerve growth factor (NGF), Neurotrophin-3 (NT-3) and Neurotrophin-4 (NT-4) were cleaved by KLK6 at the same position expected by furin. Finally, KLK6 cleaved FRET peptides derived from human proenkephalin after the KR, the more frequent basic residues flanking enkephalins in human proenkephalin sequence. This result suggests the ability of KLK6 to release enkephalin from proenkephalin precursors and resembles furin a canonical processing proteolytic enzyme. Molecular models of peptides were built into the KLK6 structure and the marked preference of the cut between the two R of the examined peptides was related to the extended conformation of the substrates.
机译:人激肽释放酶6(KLK6)在中枢神经系统中高度表达,并在脱髓鞘疾病中水平升高。 KLK6对精氨酸(R)具有非常有限的特异性,并且水解髓磷脂碱性蛋白,蛋白激活剂受体和人离子型谷氨酸受体亚基。在这里,我们报告了先前未报道的KLK6在含有碱性氨基酸簇的肽上的活性,如合成的荧光肽基-Arg-7-氨基-4-氨基甲酰基甲基香豆素(肽基-ACC)肽和FRET肽,其形式为Abz-肽基- Q-EDDnp(其中Abz =正氨基苯甲酸,Q-EDDnp =谷氨酰胺基-N-(2,4-二硝基苯基)乙二胺),其中引入了成对或碱性氨基酸(R或K)的序列。令人惊讶地,KLK6水解了两个R基团之间的荧光肽Bz-A-R(↓)R-ACC和Z-R(↓)R-MCA,从而产生了非荧光产物。含有人MMP-14,神经生长因子(NGF),Neurotrophin-3(NT-3)和Neurotrophin-4(NT-4)弗林蛋白酶加工序列的FRET肽在弗林蛋白酶预期的相同位置被KLK6切割。最后,在KR之后,KLK6裂解了源自人脑啡肽的FRET肽,即人脑啡肽序列中侧脑啡肽的频率更高的碱性残基。该结果表明KLK6能够从前脑啡肽前体释放脑啡肽的能力,并且类似于弗林蛋白酶(一种典型的加工蛋白水解酶)。肽的分子模型建立在KLK6结构中,被检测肽的两个R之间切割的明显偏好与底物的扩展构象有关。

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