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AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes
The mammalian high mobility group protein AT-hook 2 (HMGA2) houses three motifs that preferentially bind short stretches of AT-rich DNA regions. These DNA binding motifs, known as ‘AT-hooks’, are traditionally characterized as being unstructured. Upon binding to AT-rich DNA, they form ordered assemb...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Oxford University Press
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934665/ https://www.ncbi.nlm.nih.gov/pubmed/35212375 http://dx.doi.org/10.1093/nar/gkac115 |
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author | Garabedian, Alyssa Jeanne Dit Fouque, Kevin Chapagain, Prem P Leng, Fenfei Fernandez-Lima, Francisco |
author_facet | Garabedian, Alyssa Jeanne Dit Fouque, Kevin Chapagain, Prem P Leng, Fenfei Fernandez-Lima, Francisco |
author_sort | Garabedian, Alyssa |
collection | PubMed |
description | The mammalian high mobility group protein AT-hook 2 (HMGA2) houses three motifs that preferentially bind short stretches of AT-rich DNA regions. These DNA binding motifs, known as ‘AT-hooks’, are traditionally characterized as being unstructured. Upon binding to AT-rich DNA, they form ordered assemblies. It is this disordered-to-ordered transition that has implicated HMGA2 as a protein actively involved in many biological processes, with abnormal HMGA expression linked to a variety of health problems including diabetes, obesity, and oncogenesis. In the current work, the solution binding dynamics of the three ‘AT-hook’ peptides (ATHPs) with AT-rich DNA hairpin substrates were studied using DNA UV melting studies, fluorescence spectroscopy, native ion mobility spectrometry-mass spectrometry (IMS-MS), solution isothermal titration calorimetry (ITC) and molecular modeling. Results showed that the ATHPs bind to the DNA to form a single, 1:1 and 2:1, ‘key-locked’ conformational ensemble. The molecular models showed that 1:1 and 2:1 complex formation is driven by the capacity of the ATHPs to bind to the minor and major grooves of the AT-rich DNA oligomers. Complementary solution ITC results confirmed that the 2:1 stoichiometry of ATHP: DNA is originated under native conditions in solution. |
format | Online Article Text |
id | pubmed-8934665 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-89346652022-03-21 AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes Garabedian, Alyssa Jeanne Dit Fouque, Kevin Chapagain, Prem P Leng, Fenfei Fernandez-Lima, Francisco Nucleic Acids Res Chemical Biology and Nucleic Acid Chemistry The mammalian high mobility group protein AT-hook 2 (HMGA2) houses three motifs that preferentially bind short stretches of AT-rich DNA regions. These DNA binding motifs, known as ‘AT-hooks’, are traditionally characterized as being unstructured. Upon binding to AT-rich DNA, they form ordered assemblies. It is this disordered-to-ordered transition that has implicated HMGA2 as a protein actively involved in many biological processes, with abnormal HMGA expression linked to a variety of health problems including diabetes, obesity, and oncogenesis. In the current work, the solution binding dynamics of the three ‘AT-hook’ peptides (ATHPs) with AT-rich DNA hairpin substrates were studied using DNA UV melting studies, fluorescence spectroscopy, native ion mobility spectrometry-mass spectrometry (IMS-MS), solution isothermal titration calorimetry (ITC) and molecular modeling. Results showed that the ATHPs bind to the DNA to form a single, 1:1 and 2:1, ‘key-locked’ conformational ensemble. The molecular models showed that 1:1 and 2:1 complex formation is driven by the capacity of the ATHPs to bind to the minor and major grooves of the AT-rich DNA oligomers. Complementary solution ITC results confirmed that the 2:1 stoichiometry of ATHP: DNA is originated under native conditions in solution. Oxford University Press 2022-02-25 /pmc/articles/PMC8934665/ /pubmed/35212375 http://dx.doi.org/10.1093/nar/gkac115 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Chemical Biology and Nucleic Acid Chemistry Garabedian, Alyssa Jeanne Dit Fouque, Kevin Chapagain, Prem P Leng, Fenfei Fernandez-Lima, Francisco AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes |
title | AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes |
title_full | AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes |
title_fullStr | AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes |
title_full_unstemmed | AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes |
title_short | AT-hook peptides bind the major and minor groove of AT-rich DNA duplexes |
title_sort | at-hook peptides bind the major and minor groove of at-rich dna duplexes |
topic | Chemical Biology and Nucleic Acid Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8934665/ https://www.ncbi.nlm.nih.gov/pubmed/35212375 http://dx.doi.org/10.1093/nar/gkac115 |
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