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TitleAbl2 repairs microtubules and phase separates with tubulin to promote microtubule nucleation.
Journal, issue, pagesCurr Biol, Vol. 33, Issue 21, Page 4582-4598.e10, Year 2023
Publish dateNov 6, 2023
AuthorsDaisy Duan / Wanqing Lyu / Pengxin Chai / Shaojie Ma / Kuanlin Wu / Chunxiang Wu / Yong Xiong / Nenad Sestan / Kai Zhang / Anthony J Koleske /
PubMed AbstractAbl family kinases are evolutionarily conserved regulators of cell migration and morphogenesis. Genetic experiments in Drosophila suggest that Abl family kinases interact functionally with ...Abl family kinases are evolutionarily conserved regulators of cell migration and morphogenesis. Genetic experiments in Drosophila suggest that Abl family kinases interact functionally with microtubules to regulate axon guidance and neuronal morphogenesis. Vertebrate Abl2 binds to microtubules and promotes their plus-end elongation, both in vitro and in cells, but the molecular mechanisms by which Abl2 regulates microtubule (MT) dynamics are unclear. We report here that Abl2 regulates MT assembly via condensation and direct interactions with both the MT lattice and tubulin dimers. We find that Abl2 promotes MT nucleation, which is further facilitated by the ability of the Abl2 C-terminal half to undergo liquid-liquid phase separation (LLPS) and form co-condensates with tubulin. Abl2 binds to regions adjacent to MT damage, facilitates MT repair via fresh tubulin recruitment, and increases MT rescue frequency and lifetime. Cryo-EM analyses strongly support a model in which Abl2 engages tubulin C-terminal tails along an extended MT lattice conformation at damage sites to facilitate repair via fresh tubulin recruitment. Abl2Δ688-790, which closely mimics a naturally occurring splice isoform, retains binding to the MT lattice but does not bind tubulin, promote MT nucleation, or increase rescue frequency. In COS-7 cells, MT reassembly after nocodazole treatment is greatly slowed in Abl2 knockout COS-7 cells compared with wild-type cells, and these defects are rescued by re-expression of Abl2, but not Abl2Δ688-790. We propose that Abl2 locally concentrates tubulin to promote MT nucleation and recruits it to defects in the MT lattice to enable repair and rescue.
External linksCurr Biol / PubMed:37858340 / PubMed Central
MethodsEM (helical sym.)
Resolution3.8 - 4.0 Å
Structure data

EMDB-41167: GMPCPP-microtubule C1 reconstruction
Method: EM (helical sym.) / Resolution: 4.0 Å

EMDB-41169: GMPCPP-microtubule decorated with Abl2-557-1090
Method: EM (helical sym.) / Resolution: 4.0 Å

EMDB-41170: Protofilament reconstruction of microtubule decorated with Abl2-557-1090 (consensus map)
Method: EM (helical sym.) / Resolution: 3.8 Å

EMDB-41173: Protofilament reconstruction of microtubule decorated with Abl2-557-1090, Class 1
Method: EM (helical sym.) / Resolution: 4.0 Å

EMDB-41176: Protofilament reconstruction of microtubule decorated with Abl2-557-1090, Class 2
Method: EM (helical sym.) / Resolution: 4.0 Å

EMDB-41177: Protofilament reconstruction of microtubule decorated with Abl2-557-1090, Class 3
Method: EM (helical sym.) / Resolution: 4.0 Å

Source
  • Sus scrofa (pig)
  • Homo sapiens (human)

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