Regulating peroxisome–ER contacts via the ACBD5-VAPB tether by FFAT motif phosphorylation and GSK3β
| Autor: | Christian Hacker, Suzan Kors, Emily J.A. Kitchener, Renate Maier, Joseph L. Costello, Michael Schrader, Bettina Warscheid, Lena Reimann, Chloe Bolton |
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| Rok vydání: | 2022 |
| Předmět: |
Protein domain
Amino Acid Motifs Vesicular Transport Proteins Endoplasmic Reticulum Biochemistry Article Cell Line Mice Phosphoserine Peroxisomes Animals Humans Phosphorylation Glycogen synthase Adaptor Proteins Signal Transducing Organelles Glycogen Synthase Kinase 3 beta biology Chemistry Endoplasmic reticulum Membrane and Lipid Biology Membrane Proteins Cell Biology VAPB Peroxisome Cell biology Major sperm protein Membrane Mutation biology.protein Protein Binding |
| Zdroj: | The Journal of Cell Biology |
| ISSN: | 1540-8140 0021-9525 |
| DOI: | 10.1083/jcb.202003143 |
| Popis: | Kors et al. reveal that peroxisome–ER associations via the ACBD5-VAPB tether are regulated by phosphorylation and GSK3β in mammalian cells. Phosphorylation sites in the FFAT-like motif of ACBD5 affect the binding to VAPB—and thus peroxisome–ER contact sites—differently. 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 GSK3β (glycogen synthase kinase-3 β) 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. |
| Databáze: | OpenAIRE |
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