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| Title | HURP binding to the vinca domain of β-tubulin accounts for cancer drug resistance. |
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| Journal, issue, pages | Nat Commun, Vol. 15, Issue 1, Page 8844, Year 2024 |
| Publish date | Oct 14, 2024 |
Authors | Athira Saju / Po-Pang Chen / Tzu-Han Weng / Su-Yi Tsai / Akihiro Tanaka / Yu-Ting Tseng / Chih-Chia Chang / Chun-Hsiung Wang / Yuta Shimamoto / Kuo-Chiang Hsia / ![]() |
| PubMed Abstract | Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule- ...Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule-associated protein displaying heightened expression across various cancer types, reduces cancer cells' sensitivity to vinca-alkaloid drugs upon overexpression. However, the molecular basis behind this drug resistance remains unknown. Here we discover a tubulin-binding domain within HURP, and establish its role in regulating microtubule growth. Cryo-EM analysis reveals interactions between HURP's tubulin-binding domain and the vinca domain on β-tubulin -- the site targeted by vinca alkaloid drugs. Importantly, HURP competes directly with vinorelbine, a vinca alkaloid-based chemotherapeutic agent, countering microtubule growth defects caused by vinorelbine both in vitro and in vivo. Our findings elucidate a mechanism driving drug resistance in HURP-overexpressing cancer cells and emphasize HURP tubulin-binding domain's role in mitotic spindle assembly. This underscores its potential as a therapeutic target to improve cancer treatment. |
External links | Nat Commun / PubMed:39397030 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 3.54 - 3.59 Å |
| Structure data | EMDB-38178, PDB-8x9p: ![]() EMDB-38179: Focus refinement of HURP-alpha-beta-tubulin ![]() EMDB-38180: Focus refinement HURP-alpha-beta tubulin ![]() EMDB-38181: HURP (428-534)-alpha-tubulin-beta-tubulin complex |
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Keywords | CELL CYCLE / HURP / tubulin / drug resistance / mitosis |
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homo sapiens (human)
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