Department of Biochemistry and Systems Biology, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Liverpool, UK.
Proteins. 2023 Apr;91(4):439-455. doi: 10.1002/prot.26446. Epub 2022 Dec 5.
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.
VPS13 蛋白家族构成了一类新型的桥接脂质转移酶。VPS13 基因突变的常染色体隐性遗传与人类神经退行性疾病的发生有关。生物信息学方法先前已经识别了这些蛋白质的结构域架构。在这项研究中，我们模拟了四个人类同源物 VPS13A、VPS13B、VPS13C 和 VPS13D 与模型膜的首次全长结构，以研究它们的脂质转移能力和与膜小叶的潜在结构关联。我们分析了这些蛋白质的进化保守性和物理化学性质，重点关注保守的 C 端两亲性螺旋，这些螺旋扰乱了细胞器表面，并且连接在一起，类似于传统的威尼斯贡多拉。贡多拉结构域与脂滴表面结合蛋白具有显著的结构同源性。我们引入了计算蛋白质-膜模型，显示了 VPS13A、VPS13B、VPS13C 和 VPS13D 与供体和靶膜的结合方式，并提出了蛋白质介导的脂质转移的潜在作用模型。
