The middle lipin domain adopts a membrane-binding dimeric protein fold

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Lipins are key regulators of phospholipid synthesis and triglyceride storage.
• Their enzymatic phosphatidic acid phosphatase (PAP) activity necessitates membrane association.

Purpose of the Study:

• To elucidate the structural and functional role of the conserved M-Lip domain in lipin 1.
• To understand how lipins interact with cellular membranes.

Main Methods:

• Hydrogen deuterium exchange mass spectrometry (HDX-MS) to map membrane-binding regions.
• X-ray crystallography to determine the structure of the M-Lip domain.
• In vitro and cellular assays to assess M-Lip domain function.

Main Results:

• Mouse lipin 1 membrane association involves its N-terminal helix, Ig-like domain, catalytic core, and the M-Lip domain.
• The M-Lip domain possesses a novel dimeric fold and independently binds membranes via conserved residues.
• Deletion of the M-Lip domain impairs PAP activity, membrane binding, oligomerization, and adipocyte differentiation acceleration.

Conclusions:

• The M-Lip domain is a critical, conserved structural element for mammalian lipin function.
• It acts as a membrane-binding module and influences lipin oligomerization and enzymatic activity.