1.R.2. The Bridge-like Lipid Transfer Protein (BLTP) Family

BLTP3B or SHIP164 of 1464 aas and 0 - 2 TMSs. Cellular membranes differ in protein and lipid compositions as well as in the protein-lipid ratio. Progression of membranous organelles along traffic routes requires mechanisms to control bilayer lipid chemistry and their abundance relative to proteins. Structural and functional characterization of VPS13-family proteins has suggested a mechanism through which lipids can be transferred in bulk from one membrane to another at membrane contact sites, and thus independently of vesicular traffic. Hanna et al. 2022 showed that SHIP164 (UHRF1BP1L) shares structural and lipid transfer properties with these proteins and is localized on a subpopulation of vesicle clusters in the early endocytic pathway whose membrane cargo includes the cation-independent mannose- 6-phosphate receptor (MPR). Loss of SHIP164 disrupts retrograde traffic of these organelles to the Golgi complex. These findings raise the possibility that bulk transfer of lipids to endocytic membranes may play a role in their traffic (Hanna et al. 2022). 

Chorcin of Homo sapiens is a 3,174 aas protein, possibly with two centrally located TMSs.  It is required for the formation or stabilization of ER-mitochondria contact sites which enable transfer of lipids between the ER and mitochondria (Yeshaw et al. 2019). It negatively regulates lipid droplet size and motility (Yeshaw et al. 2019) and is required for efficient lysosomal protein degradation (Muñoz-Braceras et al. 2019). Decreased Na⁺/K⁺ ATPase expression and a depolarized cell membrane is observed for neurons differentiated from Chorea-Acanthocytosis Patients (Hosseinzadeh et al. 2020). 

Bridge-like lipid-transport proteins (BLTPs) are an evolutionarily conserved family of proteins that localize to membrane-contact sites and are thought to mediate the bulk transfer of lipids from a donor membrane, typically the endoplasmic reticulum, to an acceptor membrane, such as that of the cell or an organelle (Kang et al. 2025).  Kang et al. 2025 presented the subunit composition and the cryogenic EM structure of the native LPD-3 BLTP complex isolated from transgenic C. elegans. LPD-3 folds into an elongated, rod-shaped tunnel of which the interior is filled with ordered lipid molecules that are coordinated by a track of ionizable residues that line one side of the tunnel. LPD-3 forms a complex with two previously uncharacterized proteins, one of which we have named Spigot and the other of which remains unnamed. Spigot interacts with the N-terminal end of LPD-3 where lipids are expected to enter the tunnel, and experiments in multiple model systems indicate that Spigot has a conserved role in BLTP function. Our LPD-3 complex structural data reveal protein-lipid interactions that suggest a model for how the native LPD-3 complex mediates bulk lipid transport and provides a foundation for mechanistic studies of BLTPs.