In silico modeling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms

Abstract

The VPS13 protein family constitutes a novel class of bridge-like lipid transferases. Autosomal recessive inheritance of mutations in VPS13 genes is associated with the development of neurodegenerative diseases in humans. Bioinformatic approaches previously recognized the domain architecture of these proteins. In this study, we model the first ever full-length structures of the four human homologs VPS13A, VPS13B, VPS13C, and VPS13D in association with model membranes, to investigate their lipid transfer ability and potential structural association with membrane leaflets. We analyze the evolutionary conservation and physicochemical properties of these proteins, focusing on conserved C-terminal amphipathic helices that disturb organelle surfaces and that, adjoined, resemble a traditional Venetian gondola. The gondola domains share significant structural homology with lipid droplet surface-binding proteins. We introduce in silico protein-membrane models displaying the mode of association of VPS13A, VPS13B, VPS13C, and VPS13D to donor and target membranes, and present potential models of action for protein-mediated lipid transfer.

Keywords: VPS13; interorganelle contacts; junctions; lipid transfer; membrane interaction; perilipin; protein modeling.

FIGURE 1

Architecture of the RBG domains in human VPS13 proteins (A–D). Chorein domain (orange), RBG repeats (gray). The models were studied in PyMOL.

FIGURE 2

Evolutionary conservation of the VAB domains in human VPS13s (A–D). The six β‐bladed repeats were labeled accordingly. The analysis was carried out employing the ConSurf Server, and the models were viewed in PyMOL. Darker purple‐colored residues are highly conserved and blue residues are variable in evolution.

FIGURE 3

Structural homology of the gondola domains of human VPS13 proteins (A–D) with lipid‐droplet coat proteins. VPS13 gondola (dark blue), other proteins (gold). Similarity scores obtained via FATCAT.

FIGURE 4

Association of human VPS13 proteins (A–D) with simulated donor and target membranes. In silico predictions were executed via CHARMM., , Chorein domain (orange), FFAT motif (magenta), RBG domain (gray), UBA domain (azure), VAB domain (green), SGD (black), gondola domain (dark blue), PH‐like domain (red). Lipid leaflet compositions are reported in Tables S10–S18.

FIGURE 5

Speculative “piston” and “spring” models of VPS13‐mediated intermembrane lipid transfer. The C‐terminal end of the VPS13 protein in both models was taken from our modeling of VPS13D. The “piston” model hypothesizes that VPS13 proteins are rigidly docked at the target membrane via C‐terminal interactions and the gondola domain and that the donor organelle performs upward/downward motions to free lipids for transfer. The “spring” model hypothesizes that lipid transfer occurs when both the N‐terminus and C‐terminus of VPS13 proteins are rigidly docked at their specific membranes and flow of transferring lipids is determined by compressing and relaxing the solvent‐exposed gaps of the RBG domains. The figure was created on BioRender.com.