title: The mechanism of Torsin ATPase activation.
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.
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114.
authors.forename: Rebecca S H
authors.initials: RS
authors.lastname: Brown
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114.
authors.forename: Chenguang
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Chase
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114.
authors.forename: Jimin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Biophysics & Biochemistry, Yale University, New Haven, CT 06520-8114 christian.schlieker@yale.edu.
authors.forename: Christian
authors.initials: C
authors.lastname: Schlieker
mesh_terms: D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020134:Catalytic Domain; D003067:Coenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D057809:HEK293 Cells; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D046912:Multiprotein Complexes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D003067:Coenzymes; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; D021122:Protein Subunits; C108175:TOR1A protein, human; C500006:TOR1AIP2 protein, human; D001120:Arginine; D000251:Adenosine Triphosphatases
keywords: ATPase; DYT1 dystonia; Torsin; nuclear envelope