Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Montecinos, Felipe, Loew, Maura, Chio, Tak I., Bane, Susan L., Sackett, Dan L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
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
_version_ 1784726749555195904
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
work_keys_str_mv AT montecinosfelipe interactionofcolchicinesiteligandswiththebloodcellspecificisotypeofbtubulinnotableaffinityforbenzimidazoles
AT loewmaura interactionofcolchicinesiteligandswiththebloodcellspecificisotypeofbtubulinnotableaffinityforbenzimidazoles
AT chiotaki interactionofcolchicinesiteligandswiththebloodcellspecificisotypeofbtubulinnotableaffinityforbenzimidazoles
AT banesusanl interactionofcolchicinesiteligandswiththebloodcellspecificisotypeofbtubulinnotableaffinityforbenzimidazoles
AT sackettdanl interactionofcolchicinesiteligandswiththebloodcellspecificisotypeofbtubulinnotableaffinityforbenzimidazoles