一种能够抑制等锥虫蛋白激酶a催化亚基样蛋白酶活性的新型肽的分析。

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY The Protein Journal Pub Date : 2023-09-15 DOI:10.1007/s10930-023-10153-1
Nelson A. Araujo, José Bubis
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引用次数: 0

摘要

一种26个残基的肽,具有来自锥虫亚属的蛋白激酶A(PKA)调节亚单位样蛋白的αN-螺旋基序(VAP26,序列 = VAPYFEKSESEDETALILKLLTYNVLFS),以与哺乳动物热稳定可溶性PKA抑制剂PKI类似的方式抑制等锥虫PKA催化亚单位样蛋白的酶活性。然而,VAP26不包含PKI抑制序列。对各种锥虫PKA调节亚单位样蛋白的αN-螺旋基序的生物信息学分析表明,该序列可以与PKA催化亚单位样蛋白质形成疏水性的肽-蛋白质相互作用,这可能代表了一种替代的PKA抑制机制。锥虫蛋白的αN-螺旋基序序列被证明是高度同源的,但与利什曼原虫和哺乳动物对应物的相应αN-螺旋基序显著不同。这种序列差异与所提出的αN-螺旋基序的二级结构形成了对比,后者在每个分析的调控亚基样蛋白中都是保守的。在来自锥虫蛋白的αN-螺旋基序的I234、L238和F244位置的计算机突变实验中,破坏了特定基序和蛋白质的稳定。相反,T239和Y240位置的突变稳定了基序和蛋白质。这些结果表明,锥虫蛋白的αN-螺旋基序可能与利什曼原虫和哺乳动物的进化路径不同。此外,发现稳定突变表明,新的抑制肽可能是基于锥虫PKA调节亚单位样蛋白的αN-螺旋基序设计的。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Analysis of a Novel Peptide That Is Capable of Inhibiting the Enzymatic Activity of the Protein Kinase A Catalytic Subunit-Like Protein from Trypanosoma equiperdum

A 26-residue peptide possessing the αN-helix motif of the protein kinase A (PKA) regulatory subunit-like proteins from the Trypanozoom subgenera (VAP26, sequence = VAPYFEKSEDETALILKLLTYNVLFS), was shown to inhibit the enzymatic activity of the Trypanosoma equiperdum PKA catalytic subunit-like protein, in a similar manner that the mammalian heat-stable soluble PKA inhibitor known as PKI. However, VAP26 does not contain the PKI inhibitory sequence. Bioinformatics analyzes of the αN-helix motif from various Trypanozoon PKA regulatory subunit-like proteins suggested that the sequence could form favorable peptide-protein interactions of hydrophobic nature with the PKA catalytic subunit-like protein, which possibly may represent an alternative PKA inhibitory mechanism. The sequence of the αN-helix motif of the Trypanozoon proteins was shown to be highly homologous but significantly divergent from the corresponding αN-helix motifs of their Leishmania and mammalian counterparts. This sequence divergence contrasted with the proposed secondary structure of the αN-helix motif, which appeared conserved in every analyzed regulatory subunit-like protein. In silico mutation experiments at positions I234, L238 and F244 of the αN-helix motif from the Trypanozoon proteins destabilized both the specific motif and the protein. On the contrary, mutations at positions T239 and Y240 stabilized the motif and the protein. These results suggested that the αN-helix motif from the Trypanozoon proteins probably possessed a different evolutionary path than their Leishmania and mammalian counterparts. Moreover, finding stabilizing mutations indicated that new inhibitory peptides may be designed based on the αN-helix motif from the Trypanozoon PKA regulatory subunit-like proteins.

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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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