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

eLife

Gary Brouhard¹  D Alex Crowder²  Linda Lee²  Andrej Sali³  Daniel J Saltzberg³  Claire H Edrington⁴  Sofía Cruz Tetlalmatzi⁴  David C Schriemer⁴  Atefeh Rafiei⁵ 

[1] Department of Pharmaceutical Chemistry, California Institute for Quantitative Biosciences, University of California, San Francisco, San Francisco, United States;Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, Canada;Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States;Department of Biology, McGill University, Montréal, Canada;Department of Chemistry, University of Calgary, Calgary, Canada;

关键词: Doublecortin;    microtubules;    neurons;    mass spectrometry;    integrative modeling;    electron microscopy;   

DOI  :  10.7554/eLife.66975

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown