How lamina-associated polypeptide 1 (LAP1) activates Torsin

Area of Science:

• Cell biology
• Structural biology
• Neuroscience

Background:

• Lamina-associated polypeptide 1 (LAP1) is a nuclear envelope protein.
• LAP1 interacts with Torsins, endoplasmic reticulum (ER)-localized AAA+ ATPases.
• The precise function of Torsins and their interaction with LAP1 are not fully understood.

Purpose of the Study:

• To determine the crystal structure of the perinuclear domain of human LAP1.
• To elucidate the mechanism by which LAP1 interacts with and potentially activates Torsins.
• To provide insights into the molecular basis of DYT1 primary dystonia.

Main Methods:

• X-ray crystallography to determine the structure of the LAP1 perinuclear domain.
• Biochemical assays to assess the interaction and activation of TorsinA by LAP1.
• Modeling and electron microscopy to visualize the LAP1-Torsin complex.

Main Results:

• The crystal structure of the LAP1 perinuclear domain revealed an atypical AAA+ fold.
• A conserved arginine (R563) in LAP1 is positioned similarly to the arginine finger in canonical AAA+ ATPases.
• LAP1 likely forms a heterohexameric (LAP1-Torsin)3 ring, with LAP1 activating Torsin.
• Mutation of R563 in LAP1 diminished its ability to stimulate TorsinA ATPase hydrolysis.

Conclusions:

• LAP1 acts as a Torsin activator, targeting Torsins to the nuclear envelope via a heterohexameric ring structure.
• The structural and functional insights into LAP1-Torsin interaction are crucial for understanding Torsin function.
• This study provides a molecular basis for investigating the etiology of DYT1 primary dystonia.