Scientists Reveal Tunnel Structure of Lipid-Transfer Protein in C. elegans.

Researchers from Oregon Health & Science University, in partnership with Oregon State University, have mapped the molecular structure of LPD-3, a bridge-like lipid-transfer protein (BLTP) in Caenorhabditis elegans. Their findings, published in Nature, reveal a tunnel-shaped architecture designed for large-scale lipid transport between cellular membranes.

Maintaining membrane structure relies heavily on lipids synthesized in the endoplasmic reticulum (ER). However, due to their hydrophobic nature, lipids cannot move freely through the cytoplasm, necessitating specialized transport proteins. While some lipid-transport proteins are known to shuttle small lipid quantities, BLTPs are thought to facilitate bulk lipid movement through extended tunnel-like formations between organelles. Until now, their detailed structures had been difficult to resolve due to their size and complexity.

Using cryogenic electron microscopy and mass spectrometry, scientists analyzed native LPD-3 isolated from genetically modified C. elegans strains carrying fluorescent and epitope tags. The C-terminally tagged strain, which maintained normal development and cold-stress responses, enabled purification of sufficient LPD-3 for structural and biochemical study, requiring proteins from about 60 million worms.

The resulting structural map, generated at 6.2 angstrom resolution, revealed LPD-3 as a 345-angstrom elongated tunnel with a hydrophobic interior. The tunnel contains 27 lipid molecules and three additional phospholipids embedded in its transmembrane region. Lining the tunnel are alternating acidic and basic residues that create an ionizable pathway for lipid head groups, with four hydration portals allowing cytosolic water access. Lipid molecules inside the tunnel are arranged roughly 8.4 angstroms apart, mirroring their natural spacing in membrane bilayers.

Mass spectrometry identified two auxiliary proteins associated with the LPD-3 complex. One, named Spigot, binds the N-terminal end of LPD-3 and is conserved across species. A second, termed lipid transfer auxiliary protein 2 (LTAP2), also displayed conservation but its precise location within the structure remains uncertain. Additionally, a three-helix transmembrane bundle was observed, though its identity is still unknown.

Functional studies using RNA interference demonstrated the importance of these proteins. Knockdown of spgt-1 in C. elegans resulted in a 79.1% decrease in apical actin fluorescence, while lpd-3 knockdown caused a 91.6% reduction. Similar knockdowns in Drosophila astrocytes and HeLa cells disrupted phagocytosis and ER–plasma membrane contact site formation, respectively, reinforcing the conserved role of Spigot.

This research establishes the full molecular composition and mechanism of the LPD-3 complex, illustrating how lipids are organized and transported along its internal tunnel. These insights not only advance the understanding of bulk lipid transfer but also lay groundwork for exploring diseases linked to human BLTP1 mutations, such as Alkuraya-Kučinskas syndrome, a serious neurological disorder.

By illuminating the structure of LPD-3, the study opens new paths for investigating lipid-transfer dysfunctions and potential therapeutic targets.

Source:https://phys.org/news/2025-04-lipid-tunnel-protein-elegans-revealed.html

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