How Organelle Contacts Are Regulated

A study published today in the Journal of Cell Biology reveals how organelles are able to control how much they interact and cooperate. This interaction and cooperation is essential for cells and organisms to survive.

In a previous study, University of Exeter researchers discovered that a protein at the peroxisomes called ACBD5 directly interacts with a protein at the endoplasmic reticulum called VAPB. This interaction links both organelles together and allows transfer of lipids between them. The new study revealed how this interaction is regulated at the molecular level.

“Organelles are not constantly tethered to each other, this would be disadvantageous,” said study leader Michael Schrader. "They also need to keep distance and change location in the cell to meet other organelles. Therefore, membrane contacts between organelles need to be dynamic. How membrane contacts are regulated is, however, not well understood."

“Our findings reveal how regulation of peroxisome-ER contacts in mammalian cells works and also provides one of the first clear examples for a physiological role of phosphorylation of peroxisomal proteins,” added co-study leader Joseph Costello.

The team found that a binding motif of ACBD5 (called FFAT motif), which is essential for the interaction with a protein domain of VAPB, can be phosphorylated at multiple amino acids. Remarkably, phosphorylation at only one amino acid in the core region of the FFAT motif blocks binding of ACBD5 to VAPB and inhibits peroxisome-ER membrane contacts.

In addition, the team identified the enzyme, the kinase GSK3β, which phosphorylates ACBD5 within the cell. They also identified other phosphorylation sites adjacent to the core region whose phosphorylation is promoting ACBD5-VAPB interaction, revealing a complex regulatory mechanism.

"FFAT motifs are found in many other proteins involved in VAP protein interaction at other locations in the cell," said Professor Schrader. "Our findings expand the current model of FFAT motifs and point to a general mechanism of their regulation by phosphorylation.”