9ZNX

Dimer of tubulin folding cofactors D and E bound to beta tubulin in the back to back orientation

Summary for 9ZNX

• Entry DOI: 10.2210/pdb9znx/pdb
• EMDB information: 74460
• Descriptor: Tubulin-specific chaperone E, Tubulin-specific chaperone D, Tubulin beta chain, ... (4 entities in total)
• Functional Keywords: tubulin, cofactor, microtubules, tubulin folding chaperone, cytosolic protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 488106.27

Authors

Taheri, A.,Al-bassam, J. (deposition date: 2025-12-14, release date: 2026-10-21, Last modification date: 2026-10-28)

Primary citation

Taheri, A.,Ashaduzzaman, M.,Gill, V.,Eskin, J.A.,Al-Bassam, J.
A unified mechanism for tubulin cofactors catalyzing alpha / beta-tubulin biogenesis and degradation.
Sci Adv, 12:eaee2303-eaee2303, 2026

PubMed Abstract: Microtubules polymerize from cytoplasmic pools of soluble αβ-tubulin heterodimers that support diverse cellular functions. The tubulin cofactors, TBCC, TBCD, and TBCE and the Arl2 GTPase, form TBC-DEG assemblies that regulate the assembly of α- and β-tubulin into heterodimers and their disassembly, yet their underlying mechanisms remain incompletely understood. Here, we reconstitute the human TBC-DE and TBC-DEG assemblies from eukaryotic cells copurified with monomeric β-tubulin intermediates and determine their cryo-EM structures. The structures reveal that TBC-DEG disassembles αβ-tubulin by releasing α-tubulin through a lever arm-like rotation in TBCE coupled to major conformational change in Arl2 upon its nucleotide release, while TBCD tightly holds β-tubulin. TBCD dissociates α-tubulin by refolding the β-tubulin H10-S8 loop at its intradimer interface. The TBC-DEG-β-tubulin or TBC-DE-β-tubulin assemblies undergo extensive back-to-back dimerization mediated by β-β-tubulin homodimers, formed through their dissociated H8 helices at unoccupied intradimer interfaces. Structural comparisons demonstrate that TBCE's mechanical rotation, driven by the Arl2 GTPase cycle, either delivers α-tubulin or removes it from beneath the TBCD-bound β-tubulin and is directionally regulated by TBCC stabilizing αβ-tubulin interfaces. Our findings suggest that TBC-DEG/TBCC catalyzing heterodimerization of α-tubulin with β-tubulin may have evolved to counteract β-tubulin's intrinsic tendency to form off-pathway toxic homodimers through its exposed α-tubulin-binding intradimer interface.

PubMed: 42102195
DOI: 10.1126/sciadv.aee2303

Experimental method

ELECTRON MICROSCOPY (7.6 Å)