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Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2
PKM2 is a rate-limiting enzyme in the glycolytic process and is involved in regulating tumor proliferation. Several amino acids (AAs) such as Asn, Asp, Val, and Cys have been shown to bind to the AA binding pocket of PKM2 and modulate its oligomeric state, substrate binding affinity, and activity. A...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10004559/ https://www.ncbi.nlm.nih.gov/pubmed/36897854 http://dx.doi.org/10.1371/journal.pone.0282508 |
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author | Nandi, Suparno Dey, Mishtu |
author_facet | Nandi, Suparno Dey, Mishtu |
author_sort | Nandi, Suparno |
collection | PubMed |
description | PKM2 is a rate-limiting enzyme in the glycolytic process and is involved in regulating tumor proliferation. Several amino acids (AAs) such as Asn, Asp, Val, and Cys have been shown to bind to the AA binding pocket of PKM2 and modulate its oligomeric state, substrate binding affinity, and activity. Although previous studies have attributed that the main chain and side chain of bound AAs are responsible for initiating signal to regulate PKM2, the signal transduction pathway remains elusive. To identify the residues involved in signal transfer process, N70 and N75 located at two ends of a β strand connecting the active site and AA binding pocket were altered. Biochemical studies of these variants with various AA ligands (Asn, Asp, Val, and Cys), illustrate that N70 and N75, along with β1 connecting these residues are part of the signal transduction pathway between the AA binding pocket and the active site. The results demonstrate that mutation of N70 to D prevents the transfer of the inhibitory signal mediated by Val and Cys, whereas N75 to L alteration blocks the activating signal initiated by Asn and Asp. Taken together, this study confirms that N70 is one of the residues responsible for transmitting the inhibitory signal and N75 is involved in the activation signal flow. |
format | Online Article Text |
id | pubmed-10004559 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-100045592023-03-11 Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 Nandi, Suparno Dey, Mishtu PLoS One Research Article PKM2 is a rate-limiting enzyme in the glycolytic process and is involved in regulating tumor proliferation. Several amino acids (AAs) such as Asn, Asp, Val, and Cys have been shown to bind to the AA binding pocket of PKM2 and modulate its oligomeric state, substrate binding affinity, and activity. Although previous studies have attributed that the main chain and side chain of bound AAs are responsible for initiating signal to regulate PKM2, the signal transduction pathway remains elusive. To identify the residues involved in signal transfer process, N70 and N75 located at two ends of a β strand connecting the active site and AA binding pocket were altered. Biochemical studies of these variants with various AA ligands (Asn, Asp, Val, and Cys), illustrate that N70 and N75, along with β1 connecting these residues are part of the signal transduction pathway between the AA binding pocket and the active site. The results demonstrate that mutation of N70 to D prevents the transfer of the inhibitory signal mediated by Val and Cys, whereas N75 to L alteration blocks the activating signal initiated by Asn and Asp. Taken together, this study confirms that N70 is one of the residues responsible for transmitting the inhibitory signal and N75 is involved in the activation signal flow. Public Library of Science 2023-03-10 /pmc/articles/PMC10004559/ /pubmed/36897854 http://dx.doi.org/10.1371/journal.pone.0282508 Text en © 2023 Nandi, Dey 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 use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Nandi, Suparno Dey, Mishtu Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 |
title | Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 |
title_full | Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 |
title_fullStr | Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 |
title_full_unstemmed | Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 |
title_short | Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 |
title_sort | identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10004559/ https://www.ncbi.nlm.nih.gov/pubmed/36897854 http://dx.doi.org/10.1371/journal.pone.0282508 |
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