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.

An Autopsy Series of Seven Cases of VPS13A Disease (Chorea‐Acanthocytosis)

“…18 Impairment of phosphorylation was noted in erythrocytes from patients with VPS13A disease. 46 Recently, in silico prediction models have provided further details of the structure and apparent function of VPS13A in lipid transport between subcellular organelles, 13,47 as part of the group of related proteins (BLTPs) fulfilling similar functions. 8,9 An ongoing lipidomics study by our group (including cases 1-4 in this study) demonstrated elevated levels of bis(monoacylglycerol) phosphate, sulfatide, lysophosphatidylserine, and phosphatidylcholine in the CN and putamen, but not in the DLPFC, of human brain tissue.…”

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).…”

Phylogenetic and Structural Analyses of VPS13 Proteins in Archaeplastida Reveal Their Complex Evolutionary History in Viridiplantae

“…Another intriguing point is the domain organization of VPS13B orthologues. Whereas the Chorein and RBG2 domains as well as the C-term part of VPS13B orthologues, including the VAB domain, appeared well conserved in terms of domain and structure, we failed to detect seven of the RBG domains predicted in HsVPS13 between RBG2 and RBG10 (Levine, 2022;Dall'Armellina et al, 2023). In contrast, this region is mostly composed of helices and unstructured loops, raising questions about their general structure and function conservation (Figure S7).…”

“…VPS13B. In human, VPS13B is composed of 13 RBG repeats and contains the four VPS13 canonical domains and a β-sandwich domain inserted between the RBG10 and 11 (Levine, 2022;Dall'Armellina et al, 2023). In Viridiplantae, the Chorein, VAB, and ATG2_C are also found.…”