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Hypothetical model of the yeast Atg21 complex involved in Atg8-lipidation based on the structure of K. lactis Atg21 in complex with the coiled-coil domain of A. gossypii Atg16 (Munzel et al. 2021). Atg16 forms a complex with Atg5 and Atg12, acting as an E3 during Atg8 lipidation. Atg21 acts as a scaffold for recruiting Atg8 in conjugation with Atg3 to the top side of the PROPPIN (Juris et al. 2015).
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Atg18, Atg21 and Hsv2 are homologous β-propeller proteins binding to PI3P and PI(3,5)P2. Atg18 is thought to organize lipid transferring protein complexes at contact sites of the growing autophagosome (phagophore) with both the ER and the vacuole. Atg21 is restricted to the vacuole phagophore contact, where it organizes part of the Atg8-lipidation...
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Lipid droplets (LDs) are organelles critical for energy storage and membrane lipid homeostasis, whose number and size are carefully regulated in response to cellular conditions. The molecular mechanisms underlying lipid droplet biogenesis and degradation, however, are not well understood. The Troyer syndrome protein spartin (SPG20) supports LD deli...
Citations
... To our knowledge, the PROPPIN family is the only phospholipid-binding domain characterized by a b-propeller structure with a unique ability to bind phosphatidylinositol phosphates (PIPs) such as PI(3)P and PI(3,5)P2 (40). PROPPINs are endomembrane-localizing scaffold proteins for assembling protein complexes, such as autophagy machinery components (41). PROPPINs initially target membranes through nonspecific electrostatic interactions, followed by retention via PIP binding to two specific sites and membrane insertion of loop 6CD (42). ...
Placental development is regulated by the balance between cell proliferation and death. The placental protein NRK (NIK-related kinase) plays a role in preventing excessive placenta growth. We previously demonstrated that NRK underwent rapid molecular evolution in the ancestor of placental mammals and acquired the functional regions, including the phospholipid-binding citron homology (CNH) domain, by which NRK inhibits cell proliferation. NRK is also potentially responsible for cell death; caspases cleave NRK during apoptosis, releasing the C- terminal fragment that promotes cell death. Here, we explored the molecular mechanisms underlying the cell death-promoting effects of NRK. Our experimental data using HeLa, placenta trophoblast BeWo (human), and Rcho-1 (rat) cells indicated that the CNH domain of NRK was required and sufficient to promote cell death. In vitro and in silico studies showed the NRK CNH domain bound to phospholipids via its polybasic clusters and remains at the plasma membrane (PM) during apoptosis. Evolutional analyses indicated that these clusters formed in the ancestor of placental mammals. Mutations in these clusters (CNH-18A) hindered the cell death-promoting activity of the CNH domain. We concluded that NRK promotes cell death through its plasma membrane-localizing CNH domain and suggested its active role in PM-associated events during cell death.
... Macroautophagy (hereafter autophagy) delivers superfluous or damaged cytosolic material, including parts of organelles, for degradation to the lysosome (vacuole). Autophagy and its molecular machinery are highly conserved from yeast to humans and have attracted great medical interest [1][2][3][4]. In S. cerevisiae, which was used in this project, autophagy starts with the de novo assembly of double-membraned phagophores (isolation membranes). ...
The putative phospholipase Atg15 is required for the intravacuolar lysis of autophagic bodies and MVB vesicles. Intracellular membrane lysis is a highly sophisticated mechanism that is not fully understood. The amino-terminal transmembrane domain of Atg15 contains the sorting signal for entry into the MVB pathway. By replacing this domain, we generated chimeras located in the cytosol, the vacuole membrane, and the lumen. The variants at the vacuole membrane and in the lumen were highly active. Together with the absence of Atg15 from the phagophore and autophagic bodies, this suggests that, within the vacuole, Atg15 can lyse vesicles where it is not embedded. In-depth topological analyses showed that Atg15 is a single membrane-spanning protein with the amino-terminus in the cytosol and the rest, including the active site motif, in the ER lumen. Remarkably, only membrane-embedded Atg15 variants affected growth when overexpressed. The growth defects depended on its active site serine 332, showing that it was linked to the enzymatic activity of Atg15. Interestingly, the growth defects were independent of vacuolar proteinase A and vacuolar acidification.
PROPPINs constitute a conserved protein family with multiple members being expressed in many eukaryotes. PROPPINs have mainly been investigated for their role in autophagy, where they co-operate with several core factors for autophagosome formation. Recently, novel functions of these proteins on endo-lysosomal compartments have emerged. PROPPINs support the division of these organelles and the formation of tubulo-vesicular cargo carriers that mediate protein exit from them, such as those generated by the Retromer coat. In both cases, PROPPINs provide membrane fission activity. Integrating information from yeast and human cells this review summarizes the most important molecular features that allow these proteins to facilitate membrane fission and thus provide a critical element to endo-lysosomal protein traffic.
The four human WIPI β‐propellers, WIPI1 through WIPI4, belong to the ancient PROPPIN family and fulfill scaffold functions in the control of autophagy. In this context, WIPI β‐propellers function as PI3P effectors during autophagosome formation and loss of WIPI function negatively impacts autophagy and contributes to neurodegeneration. Of particular interest are mutations in WDR45 , the human gene that encodes WIPI4. Sporadic WDR45 mutations are the cause of a rare human neurodegenerative disease called BPAN, hallmarked by high brain iron accumulation. Here we discuss the current understanding of the functions of human WIPI β‐propellers and address unanswered questions with a particular focus on the role of WIPI4 in autophagy and BPAN.
