Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 45, Pages E4822-E4831Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1415271111
Keywords
DYT1 dystonia; nuclear envelope; ATPase; Torsin
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Funding
- Ellison Medical Foundation [AG-NS-0662-10]
- NIH [DP2 OD008624-01, P01 GM022778]
- Steitz Center for Structural Biology, Gwangju Institute of Science and Technology, Republic of Korea
- National Science Foundation Graduate Research Fellowship
- [5T32GM007223-39]
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Torsins are membrane-associated ATPases whose activity is dependent on two activating cofactors, lamina-associated polypeptide 1 (LAP1) and luminal domain-like LAP1 (LULL1). The mechanism bywhich these cofactors regulate Torsin activity has so far remained elusive. In this study, we identify a conserved domain in these activators that is predicted to adopt a fold resembling an AAA+ (ATPase associated with a variety of cellular activities) domain. Within these domains, a strictly conserved Arg residue present in both activating cofactors, but notably missing in Torsins, aligns with a key catalytic Arg found in AAA+ proteins. We demonstrate that cofactors and Torsins associate to form heterooligomeric assemblies with a defined Torsin-activator interface. In this arrangement, the highly conserved Arg residue present in either cofactor comes into close proximity with the nucleotide bound in the neighboring Torsin subunit. Because this invariant Arg is strictly required to stimulate Torsin ATPase activity but is dispensable for Torsin binding, we propose that LAP1 and LULL1 regulate Torsin ATPase activity through an active site complementation mechanism.
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