Regulation of Torsin ATPases by LAP1 and LULL1

Abstract

TorsinA is a membrane-associated AAA+ (ATPases associated with a variety of cellular activities) ATPase implicated in primary dystonia, an autosomal-dominant movement disorder. We reconstituted TorsinA and its cofactors in vitro and show that TorsinA does not display ATPase activity in isolation; ATP hydrolysis is induced upon association with LAP1 and LULL1, type II transmembrane proteins residing in the nuclear envelope and endoplasmic reticulum. This interaction requires TorsinA to be in the ATP-bound state, and can be attributed to the luminal domains of LAP1 and LULL1. This ATPase activator function controls the activities of other members of the Torsin family in distinct fashion, leading to an acceleration of the hydrolysis step by up to two orders of magnitude. The dystonia-causing mutant of TorsinA is defective in this activation mechanism, suggesting a loss-of-function mechanism for this congenital disorder.DYT1 dystonia | LINC complex | nuclear egress

Mutation in TOR1AIP1 encoding LAP1B in a form of muscular dystrophy: A novel gene related to nuclear envelopathies

“…On the other hand, overexpression of LAP1 and LULL1 recruits torsinA to the nuclear envelope [11,28]. A recent study reported that ATPase activity of torsinA is induced in the presence of LAP1 or LULL1 and that LAP1 and LULL1 are regulatory cofactors of torsinA [12]. In agreement with the literature, in the present study we did not observe any change in the localization of torsinA or LULL1 in the absence of LAP1B, as compared to control muscle (see online Supplementary Fig.…”

“…LAP1B encoded by TOR1AIP1 is type-2 integral membrane protein located in the inner nuclear membrane binding both A-and B-type lamins and involved in the regulation of torsinA ATPase, a member of AAA + ATPase family (ATPases associated with a variety of cellular activities) known to be responsible for the severe movement disorder DYT1 dystonia [7][8][9][10][11][12]. TorsinA is diffusely distributed throughout the endoplasmic reticulum and the nuclear envelope continuity but some cell types exhibit a preference for the nuclear envelope [24,25].…”

“…5B). It was suggested that LAP1 and LULL1 have similar modes of action on torsinA and that regulation of its ATPase activity is dependent on the dose of its cofactors [12]. Furthermore, distribution of torsinA might be regulated by the relative abundance of its binding partners in the ER and the nuclear envelope [24].…”

“…Despite the fact that the function of LAP1B is currently not fully known, this type-2 integral membrane protein located in the inner nuclear membrane is known to bind both A-and B-type lamins [7][8][9][10]. Subsequently, LAP1 has been implicated in the regulation of torsinA ATPase which is known to cause the severe movement disorder DYT1 dystonia (MIM 128100) [11,12]. Another torsinA-interacting protein, luminal domain-like LAP1 (LULL1) encoded by TOR1AIP2 is located in the endoplasmic reticulum and shares homologous C-terminal regions with LAP1 allowing interaction with torsinA.…”

Rapid Genotyping of Animals Followed by Establishing Primary Cultures of Brain Neurons

“…The labels remained clearly visible at 3 weeks ('3-week-old') and 32 weeks of age ('32-week-old'). The individual mice can be uniquely identified by a combination of tattoos on the four paws (numbers [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] and by the information about the animal cage, or more complex numbering schemes (not shown).…”