Zusammenfassung
Peroxisomes and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism. They form membrane contacts through interaction of the peroxisomal membrane protein ACBD5 (acyl-coenzyme A-binding domain protein 5) and the ER-resident protein VAPB (vesicle-associated membrane protein-associated protein B). ACBD5 binds to the major sperm protein domain of VAPB via its FFAT-like (two phenylalanines FF in an acidic tract) motif. However, molecular mechanisms, which regulate formation of these membrane contact sites, are unknown. Here, we reveal that peroxisome-ER associations via the ACBD5-VAPB tether are regulated by phosphorylation. We show that ACBD5-VAPB binding is phosphatase-sensitive and identify phosphorylation sites in the flanking regions and core of the FFAT-like motif, which alter interaction with VAPB-and thus peroxisome-ER contact sites-differently. Moreover, we demonstrate that GSK3$\beta$ (glycogen synthase kinase-3 $\beta$) regulates this interaction. Our findings reveal for the first time a molecular mechanism for the regulation of peroxisome-ER contacts in mammalian cells and expand the current model of FFAT motifs and VAP interaction.
- 3
- acid
- adaptor
- beta/*metabolism,humans,membrane
- binding,to_read,vesicular
- kinase
- line,endoplasmic
- motifs,animals,cell
- proteins
- proteins/*chemistry/genetics/*metabolism,mice,mutation/genetics,peroxisomes/*metabolism/ultrastructure,phosphorylation,phosphoserine/metabolism,protein
- proteins/*metabolism
- reticulum/*metabolism/ultrastructure,glycogen
- signal
- synthase
- transducing/*chemistry/genetics/*metabolism,amino
- transport
Nutzer