{"title":"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。","authors":"Nelson A. Araujo, José Bubis","doi":"10.1007/s10930-023-10153-1","DOIUrl":null,"url":null,"abstract":"<div><p>A 26-residue peptide possessing the αN-helix motif of the protein kinase A (PKA) regulatory subunit-like proteins from the <i>Trypanozoom</i> subgenera (VAP26, sequence = VAPYFEKSEDETALILKLLTYNVLFS), was shown to inhibit the enzymatic activity of the <i>Trypanosoma equiperdum</i> 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 <i>Trypanozoon</i> 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 <i>Trypanozoon</i> proteins was shown to be highly homologous but significantly divergent from the corresponding αN-helix motifs of their <i>Leishmania</i> 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 <i>Trypanozoon</i> 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 <i>Trypanozoon</i> proteins probably possessed a different evolutionary path than their <i>Leishmania</i> and mammalian counterparts. Moreover, finding stabilizing mutations indicated that new inhibitory peptides may be designed based on the αN-helix motif from the <i>Trypanozoon</i> PKA regulatory subunit-like proteins.</p><h3>Graphical Abstract</h3>\n <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\n </div>","PeriodicalId":793,"journal":{"name":"The Protein Journal","volume":null,"pages":null},"PeriodicalIF":1.9000,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"Nelson A. Araujo, José Bubis\",\"doi\":\"10.1007/s10930-023-10153-1\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>A 26-residue peptide possessing the αN-helix motif of the protein kinase A (PKA) regulatory subunit-like proteins from the <i>Trypanozoom</i> subgenera (VAP26, sequence = VAPYFEKSEDETALILKLLTYNVLFS), was shown to inhibit the enzymatic activity of the <i>Trypanosoma equiperdum</i> 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 <i>Trypanozoon</i> 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 <i>Trypanozoon</i> proteins was shown to be highly homologous but significantly divergent from the corresponding αN-helix motifs of their <i>Leishmania</i> 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 <i>Trypanozoon</i> 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 <i>Trypanozoon</i> proteins probably possessed a different evolutionary path than their <i>Leishmania</i> and mammalian counterparts. Moreover, finding stabilizing mutations indicated that new inhibitory peptides may be designed based on the αN-helix motif from the <i>Trypanozoon</i> PKA regulatory subunit-like proteins.</p><h3>Graphical Abstract</h3>\\n <div><figure><div><div><picture><source><img></source></picture></div></div></figure></div>\\n </div>\",\"PeriodicalId\":793,\"journal\":{\"name\":\"The Protein Journal\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.9000,\"publicationDate\":\"2023-09-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Protein Journal\",\"FirstCategoryId\":\"2\",\"ListUrlMain\":\"https://link.springer.com/article/10.1007/s10930-023-10153-1\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Protein Journal","FirstCategoryId":"2","ListUrlMain":"https://link.springer.com/article/10.1007/s10930-023-10153-1","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
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.
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.