Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain.

Atefeh Rafiei, Sofía Cruz Tetlalmatzi, Claire H Edrington, Linda Lee, D Alex Crowder, Daniel J Saltzberg, Andrej Sali, Gary Brouhard, David C Schriemer

eLife 2022 Apr 29

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Doublecortin (DCX) is a microtubule (MT)-associated protein that regulates MT structure and function during neuronal development and mutations in DCX lead to a spectrum of neurological disorders. The structural properties of MT-bound DCX that explain these disorders are incompletely determined. Here, we describe the molecular architecture of the DCX-MT complex through an integrative modeling approach that combines data from X-ray crystallography, cryo-electron microscopy, and a high-fidelity chemical crosslinking method. We demonstrate that DCX interacts with MTs through its N-terminal domain and induces a lattice-dependent self-association involving the C-terminal structured domain and its disordered tail, in a conformation that favors an open, domain-swapped state. The networked state can accommodate multiple different attachment points on the MT lattice, all of which orient the C-terminal tails away from the lattice. As numerous disease mutations cluster in the C-terminus, and regulatory phosphorylations cluster in its tail, our study shows that lattice-driven self-assembly is an important property of DCX. © 2022, Rafiei et al.

Citation

Atefeh Rafiei, Sofía Cruz Tetlalmatzi, Claire H Edrington, Linda Lee, D Alex Crowder, Daniel J Saltzberg, Andrej Sali, Gary Brouhard, David C Schriemer. Doublecortin engages the microtubule lattice through a cooperative binding mode involving its C-terminal domain. eLife. 2022 Apr 29;11