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Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):E4822-31. doi: 10.1073/pnas.1415271111. Epub 2014 Oct 28.

The mechanism of Torsin ATPase activation.

Author information

1
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114.
2
Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114 christian.schlieker@yale.edu.

Abstract

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 by which 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.

KEYWORDS:

ATPase; DYT1 dystonia; Torsin; nuclear envelope

PMID:
25352667
PMCID:
PMC4234599
DOI:
10.1073/pnas.1415271111
[Indexed for MEDLINE]
Free PMC Article

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