Cevipabulin induced abnormal tubulin protofilaments polymerization by binding to Vinblastine site and The Seventh site

Author:

Bai Peng1,Yan Wei1,Yang Jianhong1

Affiliation:

1. Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy West China Hospital, Sichuan University Chengdu China

Abstract

AbstractMicrotubules, composed of αβ‐tubulin heterodimers, are crucial targets for chemotherapeutic agents and possess eight binding sites. Our previous study identified cevipabulin as the only one agent capable of simultaneously binding to two different sites (Vinblastine site and The Seventh site). Binding to The Seventh site by cevipabulin induces tubulin degradation. This study aimed to investigate whether it is binding to the Vinblastine site and The Seventh site exhibited an interactive cellular effect. Surprisingly, we discovered that cevipabulin induced abnormal tubulin protofilaments polymerization, a previously undefined tubulin morphology, and we proved it was an interactive effect of Cevipabulin's binding to both Vinblastine site and The Seventh site. Immunofluorescence and transmission electron microscopy confirmed cevipabulin induced the formation of linear tubulin protofilaments and their subsequent aggregation into irregular tubulin aggregates. Competition binding assays and the αY224G mutation revealed that binding of cevipabulin to both sites was necessary for the tubulin protofilaments polymerization effect. Moreover, we found that co‐treatment with a microtubule stabilization agent binding the Vinblastine site and a microtubule destabilization agent binding at the intra‐dimer interface of tubulin could also induce similar tubulin protofilaments polymerization. We proposed a mechanism where a microtubule stabilization agent on the Vinblastine site enhances longitudinal interactions between tubulin dimers, while, a microtubule destabilization agent binding at the intra‐dimer interface prevents the adoption of a straight conformation of the tubulin dimer and disrupts lateral interactions between tubulins, consequently leading to tubulin protofilaments polymerization. This study reported a new inhibitor‐induced‐tubulin‐morphology‐change and would provide insight into tubulin dynamic instability and also guide further study of cevipabulin.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Cell Biology,Structural Biology

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3