Structural dissection of αβ-tubulin heterodimer assembly and disassembly by human tubulin-specific chaperones

• 成果类型: Article
• 署名作者: Seong, Yeonjae; Kim, Hyunmin; Byun, Kyumi; Park, Yeon-Woo; Roh, Soung-Hun
• 署名单位: Seoul National University (SNU); Seoul National University (SNU); European Molecular Biology Laboratory (EMBL)
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ady2708
• 发表日期: 2025-10-30
• 页码: eady2708
• 关键词: dynamic instability; FOLDING COFACTORS; protein; arl2; complex; binding; microtubules; TBCB

摘要

Microtubule assembly requires a set of chaperones known as tubulin-binding cofactors (TBCs). We used cryo-electron microscopy to visualize how human TBCD, TBCE, TBCC, and guanosine triphosphatase (GTPase) Arl2 mediate alpha beta-tubulin assembly and disassembly. We captured multiple conformational states, revealing how TBCs orchestrate tubulin heterodimer biogenesis. TBCD stabilizes monomeric beta-tubulin and scaffolds the other cofactors. Guanosine triphosphate (GTP) binding to Arl2 induces conformational changes that toggle the complex between assembly and disassembly. TBCD and TBCE guide alpha- and beta-tubulin into a partially assembled interface, and TBCC, acting as a molecular clamp, completes the heterodimer. TBCD also functions as a GTPase activating protein for beta-tubulin. beta-tubulin GTP hydrolysis is coupled to Arl2's GTPase activity, establishing a checkpoint that ensures that only fully matured heterodimers proceed. These findings provide a structural framework for tubulin heterodimer biogenesis and recycling, supporting cytoskeletal proteostasis.