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.
%0 Journal Article
%1 korsRegulatingPeroxisomeERContacts2022
%A Kors, Suzan
%A Hacker, Christian
%A Bolton, Chloe
%A Maier, Renate
%A Reimann, Lena
%A Kitchener, Emily J. A.
%A Warscheid, Bettina
%A Costello, Joseph L.
%A Schrader, Michael
%C United States
%D 2022
%J The Journal of cell biology
%K 3 Acid Adaptor 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 beta/*metabolism,Humans,Membrane
%N 3
%R 10.1083/jcb.202003143
%T Regulating Peroxisome-ER Contacts via the ACBD5-VAPB Tether by FFAT Motif Phosphorylation and GSK3$\beta$.
%V 221
%X 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.
@article{korsRegulatingPeroxisomeERContacts2022,
abstract = {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.},
added-at = {2024-05-17T13:01:35.000+0200},
address = {United States},
author = {Kors, Suzan and Hacker, Christian and Bolton, Chloe and Maier, Renate and Reimann, Lena and Kitchener, Emily J. A. and Warscheid, Bettina and Costello, Joseph L. and Schrader, Michael},
biburl = {https://www.bibsonomy.org/bibtex/25be286092f478be5de622d655af0aebd/warscheidlab},
copyright = {{\copyright} 2022 Kors et al.},
doi = {10.1083/jcb.202003143},
interhash = {7c6b573844dc4dcd059ce2ff8f748900},
intrahash = {5be286092f478be5de622d655af0aebd},
issn = {1540-8140 0021-9525},
journal = {The Journal of cell biology},
keywords = {3 Acid Adaptor 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 beta/*metabolism,Humans,Membrane},
langid = {english},
month = mar,
number = 3,
pmcid = {PMC8759595},
pmid = {35019937},
timestamp = {2024-05-17T13:01:35.000+0200},
title = {Regulating Peroxisome-{{ER}} Contacts via the {{ACBD5-VAPB}} Tether by {{FFAT}} Motif Phosphorylation and {{GSK3$\beta$}}.},
volume = 221,
year = 2022
}