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Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles
Tubulin, the main component of microtubules, is an α-β heterodimer that contains one of multiple isotypes of each monomer. Although the isotypes of each monomer are very similar, the beta tubulin isotype found in blood cells is significantly divergent in amino acid sequence compared to other beta tu...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9194530/ https://www.ncbi.nlm.nih.gov/pubmed/35712668 http://dx.doi.org/10.3389/fcell.2022.884287 |
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author | Montecinos, Felipe Loew, Maura Chio, Tak I. Bane, Susan L. Sackett, Dan L. |
author_facet | Montecinos, Felipe Loew, Maura Chio, Tak I. Bane, Susan L. Sackett, Dan L. |
author_sort | Montecinos, Felipe |
collection | PubMed |
description | Tubulin, the main component of microtubules, is an α-β heterodimer that contains one of multiple isotypes of each monomer. Although the isotypes of each monomer are very similar, the beta tubulin isotype found in blood cells is significantly divergent in amino acid sequence compared to other beta tubulins. This isotype, beta class VI, coded by human gene TUBB1, is found in hematologic cells and is recognized as playing a role in platelet biogenesis and function. Tubulin from the erythrocytes of the chicken Gallus gallus contains almost exclusively βVI tubulin. This form of tubulin has been reported to differ from brain tubulin in binding of colchicine-site ligands, previously thought to be a ubiquitous characteristic of tubulin from higher eukaryotes. In this study, we sought to gain a better understanding of the structure-activity relationship of the colchicine site of this divergent isotype, using chicken erythrocyte tubulin (CeTb) as the model. We developed a fluorescence-based assay to detect binding of drugs to the colchicine site and used it to study the interaction of 53 colchicine-site ligands with CeTb. Among the ligands known to bind at this site, most colchicine derivatives had lower affinity for CeTb compared to brain tubulin. Remarkably, many of the benzimidazole class of ligands shows increased affinity for CeTb compared to brain tubulin. Because the colchicine site of human βVI tubulin is very similar to that of chicken βVI tubulin, these results may have relevance to the effect of anti-cancer agents on hematologic tissues in humans. |
format | Online Article Text |
id | pubmed-9194530 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91945302022-06-15 Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles Montecinos, Felipe Loew, Maura Chio, Tak I. Bane, Susan L. Sackett, Dan L. Front Cell Dev Biol Cell and Developmental Biology Tubulin, the main component of microtubules, is an α-β heterodimer that contains one of multiple isotypes of each monomer. Although the isotypes of each monomer are very similar, the beta tubulin isotype found in blood cells is significantly divergent in amino acid sequence compared to other beta tubulins. This isotype, beta class VI, coded by human gene TUBB1, is found in hematologic cells and is recognized as playing a role in platelet biogenesis and function. Tubulin from the erythrocytes of the chicken Gallus gallus contains almost exclusively βVI tubulin. This form of tubulin has been reported to differ from brain tubulin in binding of colchicine-site ligands, previously thought to be a ubiquitous characteristic of tubulin from higher eukaryotes. In this study, we sought to gain a better understanding of the structure-activity relationship of the colchicine site of this divergent isotype, using chicken erythrocyte tubulin (CeTb) as the model. We developed a fluorescence-based assay to detect binding of drugs to the colchicine site and used it to study the interaction of 53 colchicine-site ligands with CeTb. Among the ligands known to bind at this site, most colchicine derivatives had lower affinity for CeTb compared to brain tubulin. Remarkably, many of the benzimidazole class of ligands shows increased affinity for CeTb compared to brain tubulin. Because the colchicine site of human βVI tubulin is very similar to that of chicken βVI tubulin, these results may have relevance to the effect of anti-cancer agents on hematologic tissues in humans. Frontiers Media S.A. 2022-05-31 /pmc/articles/PMC9194530/ /pubmed/35712668 http://dx.doi.org/10.3389/fcell.2022.884287 Text en Copyright © 2022 Montecinos, Loew, Chio, Bane and Sackett. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Cell and Developmental Biology Montecinos, Felipe Loew, Maura Chio, Tak I. Bane, Susan L. Sackett, Dan L. Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles |
title | Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles |
title_full | Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles |
title_fullStr | Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles |
title_full_unstemmed | Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles |
title_short | Interaction of Colchicine-Site Ligands With the Blood Cell-Specific Isotype of β-Tubulin—Notable Affinity for Benzimidazoles |
title_sort | interaction of colchicine-site ligands with the blood cell-specific isotype of β-tubulin—notable affinity for benzimidazoles |
topic | Cell and Developmental Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9194530/ https://www.ncbi.nlm.nih.gov/pubmed/35712668 http://dx.doi.org/10.3389/fcell.2022.884287 |
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