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

Dall'Armellina, Filippo ORCID: 0000-0002-6790-6312, Stagi, Massimiliano ORCID: 0000-0002-5827-902X and Swan, Laura E ORCID: 0000-0002-6312-6263 (2023) In silico modeling human VPS13 proteins associated with donor and target membranes suggests lipid transfer mechanisms. PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS, 91 (4). pp. 439-455.

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Official URL: http://dx.doi.org/10.1002/prot.26446

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.

Item Type:	Article
Uncontrolled Keywords:	interorganelle contacts, junctions, lipid transfer, membrane interaction, perilipin, protein modeling, VPS13
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	21 Nov 2022 14:31
Last Modified:	04 May 2023 05:08
DOI:	10.1002/prot.26446
Open Access URL:	https://doi.org/10.1002/prot.26446
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3166306