Role of VPS13, a protein with similarity to ATG2, in physiology and disease

Abstract

The evolutionarily conserved VPS13 family proteins have been implicated in several cellular processes. Mutations in each of the four human VPS13s cause neurodevelopmental or neurodegenerative disorders. Until recently, the molecular function of VPS13 remained elusive. Genetic, functional and structural studies have now revealed that VPS13 acts at contact sites between intracellular organelles to transport lipids by a novel mechanism: direct transfer between bilayers via a hydrophobic channel that spans its entire rod-like N-terminal half. Predicted similarities to the autophagy protein ATG2 suggested a similar role for ATG2 that has now been confirmed by structural and functional studies. Here, after a brief review of this evidence, we discuss what is known of human VPS13 proteins in physiology and disease.

Figure 1.. Schematic representation of VPS13 protein domains and similarity to ATG2.

The N-terminal half of VPS13 proteins, which folds into an elongated rod with a long hydrophobic groove along its length [18,21], is indicated in orange. Primary sequence similarities occur in the chorein and ATG-C domains. Portions of VPS13 corresponding to regions solved by crystallography [18] or Cryo-EM [21] in VPS13 from Chaetomiun thermophilum are indicated by brackets. The color gradient is meant to reflect the unclear C-terminal boundary of the rod solved by Cryo-EM, which may extend further. The entire ATG2 protein has structural similarities to the rod portion of VPS13, as shown by Cryo-EM [24]. The crystal structure of the N-terminal region of ATG2 (bracket) is nearly identical to the corresponding crystallized region of VPS13 [18,25]. A clear FFAT motif is present in VPS13A and VPS13C. VPS13D has an additional ubiquitin-associated domain (UBA in pink). Both yeast Vps13 and human ATG2A have LC3 interacting regions (LIR motif). The density map of the N-terminal region of VPS13 from Chaetomiun thermophilum solved by Cryo-EM is shown at top right, where the portion also solved by crystallography is shown in yellow. The “basket” is colored light blue and yellow, helices comprising the “handle” are green (from ref , reprinted with permission ©2020 Li et al. Originally published in JCB https://doi.org/10.1083/jcb.202001161).

Figure 2.. Putative organization and lipid transport mechanism of VPS13 and ATG2 at membrane contact sites.

Schematic cartoon illustrating how the N-terminal half of VPS13 and ATG2 could directly bridge two bilayers thus allowing membrane lipid flow between them. At least for VPS13A and VPS13C, the bottom membrane is represented by the ER membrane, where these two proteins are tethered via an interaction with the ER protein VAP. Anchoring to the target membrane is mediated by the WD40-L and DH-L/PH domain regions (Model based on Kumar et al. [18] and Li et al. [21]). ATG2 is proposed to have a similar organization at contacts between the ER and the pre-autophagosomal membrane. Anchoring to the target membrane is mediated by WD40 proteins ATG18/WIPI [26].

Figure 3.. VPS13 localization at membrane contact sites.

Schematic drawing illustrating the localization of VPS13A and VPS13C at contacts between the ER and either mitochondria or endosomes/lysosomes respectively. Both proteins are also localized at contacts of the ER with lipid droplets (LD).