RBG Motif Bridge-Like Lipid Transport Proteins: Structure, Functions, and Open Questions

Abstract

The life of eukaryotic cells requires the transport of lipids between membranes, which are separated by the aqueous environment of the cytosol. Vesicle-mediated traffic along the secretory and endocytic pathways and lipid transfer proteins (LTPs) cooperate in this transport. Until recently, known LTPs were shown to carry one or a few lipids at a time and were thought to mediate transport by shuttle-like mechanisms. Over the last few years, a new family of LTPs has been discovered that is defined by a repeating β-groove (RBG) rod-like structure with a hydrophobic channel running along their entire length. This structure and the localization of these proteins at membrane contact sites suggest a bridge-like mechanism of lipid transport. Mutations in some of these proteins result in neurodegenerative diseases. Here we review the known properties and well-established or putative physiological roles of these proteins, and we highlight the many questions that remain open about their functions. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 39 is October 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

VPS13B is localized at the cis-trans Golgi complex interface and is a functional partner of FAM177A1

“…1A, S1A and S1B). One distinct feature of VPS13B is the presence of an accessory folded domain, a module with a Jelly-roll fold (Dall’Armellina et al, 2022; Levine, 2022; Hanna et al, 2023), which is an outpocketing of the RBG rod just upstream of the VAB domain (shown in gray in Fig. S1A, S1B and S1C).…”

“…Most such proteins function by a piecemeal shuttle mechanism (Saheki and De Camilli, 2017; Balla et al, 2019; Wong et al, 2019; Reinisch and Prinz, 2021). Recently, however, a class of proteins thought to function by a bridge-like mechanism at these sites, and thus optimally suited for the unidirectional bulk delivery of lipids between two closely apposed membranes, has been identified (Levine, 2022; Neuman et al, 2022; Hanna et al, 2023). One such protein is Vps13 (Dziurdzik and Conibear, 2021; Leonzino et al, 2021).…”

Unbiased MD simulations characterize lipid binding to lipid transfer proteins

“…Despite the large number of lipids in the cavity, the use of an elastic network to restrain the secondary structure prevents large protein conformational changes, thus indicating that the presence of multiple lipids is compatible with the initial AF models. A similar number of lipids (15) has been proposed for ATG2A, a human ortholog of Atg2 with the same length, using structural analysis 52 . The average solvation data of the lipid tails (Fig.…”

“…For example, even when a high-resolution structure of the LTP is available, the co-transported lipids are often missing, possibly as a consequence of the dynamic behavior of lipids inside the protein cavity. In addition, only few high-resolution structures of LTPs are available, and especially for those proposed to work via a bridge-like mechanism, AlphaFold-derived models are often used to provide a mechanistic interpretation of the functional data [12][13][14][15][16][17][18][19][20][21][22] . Finally, basic mechanistic features such as the exact entry/exit pathways for the loading and unloading of the lipids from the protein remain largely unknown.…”

Bridge-like lipid transfer protein family member 2 suppresses ciliogenesis

“…Many MCS proteins associate with the ER membrane by binding to the ER-localized integral membrane proteins VAPA and VAPB (VAPA/B), and to other organelles via organelle-specific proteins. The VAPA and VAPB proteins recognize FFAT sequence motifs located within many lipid transfer proteins, however BLTP1 and BLTP2 do not possess FFAT motifs (Hanna et al, 2023). Rather, they possess a N -terminal membrane spanning segment that localizes them to the ER membrane (Castro et al, 2022; Neuman et al, 2022).…”