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首页> 外文期刊>Biochemistry >Angiotensin-Converting Enzyme 2 Ectodomain Shedding Cleavage-Site Identification: Determinants and Constraints
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Angiotensin-Converting Enzyme 2 Ectodomain Shedding Cleavage-Site Identification: Determinants and Constraints

机译：血管紧张素转换酶2 Ectodomain脱落卵裂位点鉴定：决定因素和约束条件。

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摘要

ADAM17, also known as tumor necrosis factor alpha-converting enzyme, is involved in the ectodomain shedding of many integral membrane proteins. We have previously reported that ADAM17 is able to mediate the cleavage secretion of the ectodomain of human angiotensin-converting enzyme 2 (ACE2), a functional receptor for the severe acute respiratory syndrome coronavirus. In this study, we demonstrate that purified recombinant human ADAM 17 is able to cleave a 20-amino acid peptide mimetic corresponding to the extracellular juxtamembrane region of human ACE2 between Arg(708) and Ser(709). A series of peptide analogues were also synthesized, showing that glutamate subtitution at Arg(708) and/or Arg(710) attenuated the cleavage process, while alanine substitution at Arg(708) and/or Ser(709) did not inhibit peptide cleavage by recombinant ADAM17. Analysis of CD spectra showed a minimal difference in the secondary structure of the peptide analogues in the buffer system used for the ADAM17 cleavage assay. The observation of the shedding profiles of ACE2 mutants expressing CHO-K1 and CHO-P cells indicates that the Arg(708) -> Glu(708) mutation and the Arg(708)Arg(710) -> Glu(708)Glu(710) double mutation produced increases in the amount of ACE2 shed when stimulated by phorbol ester PMA. In summary, we have demonstrated that ADAM17 is able to cleave ACE2 peptide sequence analogues between Arg(708) and Ser(709). These findings also indicate that Arg(708) and Arg(710) play a role in site recognition in the regulation of ACE2 ectodomain shedding mediated by ADAM17.
机译：ADAM17，也称为肿瘤坏死因子α转化酶，参与许多完整膜蛋白的胞外域脱落。我们以前曾报道过，ADAM17能够介导人血管紧张素转化酶2（ACE2）的胞外域的切割分泌，ACE2是严重急性呼吸系统综合症冠状病毒的功能性受体。在这项研究中，我们证明了纯化的重组人ADAM 17能够切割对应于人ACE2的Arg（708）和Ser（709）之间的人ACE2细胞外近膜区域的20个氨基酸的肽模拟物。还合成了一系列肽类似物，显示在Arg（708）和/或Arg（710）处的谷氨酸取代减弱了裂解过程，而在Arg（708）和/或Ser（709）处的丙氨酸取代却没有抑制肽的裂解。通过重组ADAM17。 CD光谱分析显示，在用于ADAM17裂解分析的缓冲液系统中，肽类似物的二级结构差异很小。观察表达CHO-K1和CHO-P细胞的ACE2突变体的脱落曲线，表明Arg（708）-> Glu（708）突变和Arg（708）Arg（710）-> Glu（708）Glu（ 710）当受佛波酯PMA刺激时，双重突变产生的ACE2释放量增加。总之，我们已经证明ADAM17能够在Arg（708）和Ser（709）之间切割ACE2肽序列类似物。这些发现还表明，Arg（708）和Arg（710）在由ADAM17介导的ACE2胞外域脱落的调控中在位点识别中起作用。

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