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). 

BLTP2/KIAA0100, a bridge-like lipid transfer protein, was reported to localize at contacts of the ER with either the plasma membrane (PM) or recycling tubular endosomes depending on the cell type. It mediates bulk lipid transport between the ER and the PM, a key function of this protein, as BLTP2 tethers the ER to tubular endosomes only after they become continuous with the PM. It also tethers the ER to macropinosomes in the process of fusing with the PM (Dai et al. 2025). Interactions underlie binding of BLTP2 to the PM, including phosphoinositides, the adaptor proteins FAM102A/FAM102B, and N-BAR domain proteins at membrane-connected tubules. The absence of BLTP2 results in the accumulation of intracellular vacuoles, many of which are connected to the PM, pointing to a role of the lipid transport function of BLTP2 in the control of PM dynamics (Dai et al. 2025).

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.

 


 

References:

AbdelAleem, A., N. Haddad, G. Al-Ettribi, A. Crunk, and A. Elsotouhy. (2023). Cohen syndrome and early-onset epileptic encephalopathy in male triplets: two disease-causing mutations in VPS13B and NAPB. Neurogenetics. [Epub: Ahead of Print]
Afridi, T.U.K., A. Fatima, H.S. Satti, Z. Akram, I.K. Yousafzai, W.B. Naeem, N. Fatima, A. Ali, Z. Iqbal, A. Khan, M. Shahzad, C. Liu, M. Toft, F. Zhang, M. Tariq, E.E. Davis, and T.N. Khan. (2024). Exome sequencing in four families with neurodevelopmental disorders: genotype-phenotype correlation and identification of novel disease-causing variants in VPS13B and RELN. Mol. Genet. Genomics 299: 55.
Amos, C., P. Xu, and P. De Camilli. (2023). Erythroid Differentiation Dependent Interaction of VPS13A with XK at the Plasma Membrane of K562 Cells. Contact (Thousand Oaks) 6: 25152564231215133.
Banerjee, S., S. Daetwyler, X. Bai, M. Michaud, J. Jouhet, S. Madhugiri, E. Johnson, C.W. Wang, R. Fiolka, A. Toulmay, and W.A. Prinz. (2024). The Vps13-like protein BLTP2 is pro-survival and regulates phosphatidylethanolamine levels in the plasma membrane to maintain its fluidity and function. bioRxiv.
Dai, A., P. Xu, C. Amos, K. Fujise, Y. Wu, H. Yang, J.N. Eisen, A. Guillén-Samander, and P. De Camilli. (2025). Multiple interactions recruit BLTP2 to ER-PM contacts to control plasma membrane dynamics. J. Cell Biol. 224:.
Duplomb, L., S. Duvet, D. Picot, G. Jego, S. El Chehadeh-Djebbar, N. Marle, N. Gigot, B. Aral, V. Carmignac, J. Thevenon, E. Lopez, J.B. Rivière, A. Klein, C. Philippe, N. Droin, E. Blair, F. Girodon, J. Donadieu, C. Bellanné-Chantelot, L. Delva, J.C. Michalski, E. Solary, L. Faivre, F. Foulquier, and C. Thauvin-Robinet. (2014). Cohen syndrome is associated with major glycosylation defects. Hum Mol Genet 23: 2391-2399.
Hanna, M.G., P.H. Suen, Y. Wu, K.M. Reinisch, and P. De Camilli. (2022). SHIP164 is a chorein motif lipid transfer protein that controls endosome-Golgi membrane traffic. J. Cell Biol. 221:.
Hosseinzadeh, Z., S. Hauser, Y. Singh, L. Pelzl, S. Schuster, Y. Sharma, P. Höflinger, N. Zacharopoulou, C. Stournaras, D.L. Rathbun, E. Zrenner, L. Schöls, and F. Lang. (2020). Decreased Na/K ATPase Expression and Depolarized Cell Membrane in Neuron.s Differentiated from Chorea-Acanthocytosis Patients. Sci Rep 10: 8391.
Kang, Y., K.S. Lehmann, H. Long, A. Jefferson, M. Purice, M. Freeman, and S. Clark. (2025). Structural basis of lipid transfer by a bridge-like lipid-transfer protein. Nature. [Epub: Ahead of Print]
Koike, S. and R. Jahn. (2019). SNAREs define targeting specificity of trafficking vesicles by combinatorial interaction with tethering factors. Nat Commun 10: 1608.
Lee, Y.K., S.K. Hwang, S.K. Lee, J.E. Yang, J.H. Kwak, H. Seo, H. Ahn, Y.S. Lee, J. Kim, C.S. Lim, B.K. Kaang, J.H. Lee, J.A. Lee, and K. Lee. (2020). Cohen Syndrome Patient iPSC-Derived Neurospheres and Forebrain-Like Glutamatergic Neuron.s Reveal Reduced Proliferation of Neural Progenitor Cells and Altered Expression of Synapse Genes. J Clin Med 9:.
Lee, Y.K., S.K. Lee, S. Choi, Y.H. Huh, J.H. Kwak, Y.S. Lee, D.J. Jang, J.H. Lee, K. Lee, B.K. Kaang, C.S. Lim, and J.A. Lee. (2020). Autophagy pathway upregulation in a human iPSC-derived neuronal model of Cohen syndrome with VPS13B missense mutations. Mol Brain 13: 69.
Muñoz-Braceras, S., A.R. Tornero-Écija, O. Vincent, and R. Escalante. (2019). VPS13A is closely associated with mitochondria and is required for efficient lysosomal degradation. Dis Model Mech 12:.
Otto, G.P., M. Razi, J. Morvan, F. Stenner, and S.A. Tooze. (2010). A novel syntaxin 6-interacting protein, SHIP164, regulates syntaxin 6-dependent sorting from early endosomes. Traffic 11: 688-705.
Seifert, W., J. Kühnisch, T. Maritzen, D. Horn, V. Haucke, and H.C. Hennies. (2011). Cohen syndrome-associated protein, COH1, is a novel, giant Golgi matrix protein required for Golgi integrity. J. Biol. Chem. 286: 37665-37675.
Seifert, W., J. Kühnisch, T. Maritzen, S. Lommatzsch, H.C. Hennies, S. Bachmann, D. Horn, and V. Haucke. (2015). Cohen syndrome-associated protein COH1 physically and functionally interacts with the small GTPase RAB6 at the Golgi complex and directs neurite outgrowth. J. Biol. Chem. 290: 3349-3358.
Yeshaw, W.M., M. van der Zwaag, F. Pinto, L.L. Lahaye, A.I. Faber, R. Gómez-Sánchez, A.M. Dolga, C. Poland, A.P. Monaco, S.C. van IJzendoorn, N.A. Grzeschik, A. Velayos-Baeza, and O.C. Sibon. (2019). Human VPS13A is associated with multiple organelles and influences mitochondrial morphology and lipid droplet motility. Elife 8:.
Examples:

TC#NameOrganismal TypeExample
1.R.2.1.1

The BLTP3B protein of 1464 aas and 0 - 2 TMSs. Also called the SHIP164 protein.  BLTP3B or SHIP164 is of 1464 aas and 0 - 2 TMSs. It is a tube-forming lipid transport protein which mediates the transfer of lipids between membranes at organelle contact sites and is required for retrograde trafficing of vesicle clusters in the early endocytic pathway to the Golgi complex (Otto et al. 2010). 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).

BLTP3B of Homo sapiens

 
1.R.2.1.2

Bridge-like lipid transfer protein family member 3A, BLTP3A, of 1440 aas and 0 - 2 TMSs.

BLTP3A of Homo sapiens

 
1.R.2.1.3

Intermembrane lipid transfer protein Vps13A; Vacuolar protein sorting-associated protein 13A of 3373 aas.  The Vps13-like protein BLTP2 is pro-survival and regulates phosphatidylethanolamine levels in the plasma membrane to maintain its fluidity and function (Banerjee et al. 2024).

Vps13A of Dictyostelium discoideum

 
1.R.2.1.4

Intermembrane lipid transfer protein, VPS13B, of 4022 aas. Mediates the transfer of lipids between membranes at organelle contact sites and binds phosphatidylinositol 3-phosphate.
It functions as a tethering factor in the slow endocytic recycling pathway, to assist traffic between early and recycling endosomes (Koike and Jahn 2019, Duplomb et al. 2014, Lee et al. 2020). It is involved in the transport of proacrosomal vesicles to the nuclear dense lamina (NDL) during spermatid development, and plays a role in the assembly of the Golgi apparatus, possibly by mediating trafficking to the Golgi membrane (Seifert et al. 2011). It plays a role in the development of the nervous system, and may be required for neuron projection development (Seifert et al. 2015, Lee et al. 2020). The pathologic mechanism underlying the expansion of the neurodevelopmental spectrum in Cohen syndrome (CS) due to mutations in VPS13B, highlight the importance of Golgi and Golgi-membrane-related proteins in the development of neurodevelopmental syndromes associated with early-onset non-channelopathy epilepsy (AbdelAleem et al. 2023).  Variants can cause neurodevelopmental disorders (Afridi et al. 2024).

VPS13B of Homo sapiens

 
1.R.2.1.5

Intermembrane lipid transfer protein, Vps13, of 3321 aas, also called vacuolar protein sorting-associated protein 13.

Vps13 of Drosophila melanogaster (fruit fly)

 
1.R.2.1.6

The chorcin (VPS13A) protein of 3174 aas and possibly several central TMSs. See family description for details of its function. The N-terminal region shows appreciable sequence similarity with members of the APT family (TC#9.A.15).  Erythroid differentiation is dependent on interactions of VPS13A with XK at the plasma membrane of K562 cells (Amos et al. 2023).

Chorcin of Homo sapiens