Abstract

Lamin-associated polypeptide 1 (LAP1) resides at the nuclear envelope and interacts with Torsins, poorly understood ER-localized AAA+ ATPases, through a conserved, perinuclear domain. We determined the crystal structure of the perinuclear domain of human LAP1. LAP1 possesses an atypical AAA+ fold. While LAP1 lacks canonical nucleotide binding motifs, its strictly conserved arginine 563 is positioned exactly where the arginine finger of canonical AAA+ ATPases is found. Based on modeling and electronmicroscopic analysis we propose that LAP1 targets Torsin to the nuclear envelope by forming an alternating, heterohexameric (LAP1-Torsin)3 ring, in which LAP1 acts as the Torsin activator. The experimental data shows that mutation of arginine 563 in LAP1 reduces its ability to stimulate TorsinA ATPase hydrolysis. This knowledge may help understand the etiology of DYT1 primary dystonia, a movement disorder caused by a single glutamate deletion in TorsinA

Article and author information

Author details

  1. Brian A Sosa

    Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  2. F Esra Demircioglu

    Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. James Z Chen

    Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    James Z Chen, Reviewing editor, eLife.
  4. Jessica Ingram

    Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  5. Hidde Ploegh

    Massachusetts Institute of Technology, Cambridge, United States
    Competing interests
    No competing interests declared.
  6. Thomas U Schwartz

    Massachusetts Institute of Technology, Cambridge, United States
    For correspondence
    tus@mit.edu
    Competing interests
    No competing interests declared.

Reviewing Editor

  1. Wesley I Sundquist, University of Utah, United States

Version history

  1. Received: April 30, 2014
  2. Accepted: August 21, 2014
  3. Accepted Manuscript published: August 22, 2014 (version 1)
  4. Version of Record published: September 18, 2014 (version 2)

Copyright

© 2014, Sosa et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Brian A Sosa
  2. F Esra Demircioglu
  3. James Z Chen
  4. Jessica Ingram
  5. Hidde Ploegh
  6. Thomas U Schwartz
(2014)
How lamina-associated polypeptide 1 (LAP1) activates Torsin
eLife 3:e03239.
https://doi.org/10.7554/eLife.03239

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https://doi.org/10.7554/eLife.03239

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