Structural Organization of the Nvj3-Mdm1 Complex Reveals a Conserved Lipid-Compatible Contact Site Module

Area of Science:

• Cell Biology
• Structural Biology
• Biochemistry

Background:

• Membrane contact sites (MCSs) coordinate organelle function and lipid metabolism via protein assemblies.
• The structural basis for lipid transfer at MCSs, like the nuclear-vacuolar junction (NVJ), is poorly understood.
• The Mdm1-Nvj3 complex at the NVJ regulates lipid metabolism, but its structure is unknown.

Purpose of the Study:

• To determine the structural organization of the Nvj3-Mdm1 complex.
• To elucidate the structural principles underlying lipid exchange at the NVJ.
• To investigate the role of the Nvj3-Mdm1 complex in inter-organelle lipid transfer.

Main Methods:

• AlphaFold-based complex prediction for Nvj3-Mdm1.
• Comparative structural analysis of protein domains.
• Tunnel analysis to predict lipid transfer pathways.
• Phylogenetic analysis of Nvj3 and Mdm1.

Main Results:

• A high-confidence Nvj3-Mdm1 heterodimer was identified.
• Conserved PXA and PXC domains form an extended tunnel across the complex.
• The predicted tunnel is hydrophobic and lipid-compatible, similar to known lipid transfer proteins.
• Evolutionary conservation is enriched at the Nvj3-Mdm1 interface.
• The conduit is α-helical, differing from canonical β-sheet-rich lipid transfer proteins.

Conclusions:

• Nvj3 is a structural partner of Mdm1 at the NVJ.
• The Nvj3-Mdm1 complex forms a lipid transfer conduit.
• This structure supports a conduit-based model for inter-organelle lipid transfer at MCSs.