RDGBα localization and function at membrane contact sites is regulated by FFAT-VAP interactions

J Cell Sci. 2018 Jan 8;131(1):jcs207985. doi: 10.1242/jcs.207985.


Phosphatidylinositol transfer proteins (PITPs) are essential regulators of PLC signalling. The PI transfer domain (PITPd) of multi-domain PITPs is reported to be sufficient for in vivo function, questioning the relevance of other domains in the protein. In Drosophila photoreceptors, loss of RDGBα, a multi-domain PITP localized to membrane contact sites (MCSs), results in multiple defects during PLC signalling. Here, we report that the PITPd of RDGBα does not localize to MCSs and fails to support function during strong PLC stimulation. We show that the MCS localization of RDGBα depends on the interaction of its FFAT motif with dVAP-A. Disruption of the FFAT motif (RDGBFF/AA) or downregulation of dVAP-A, both result in mis-localization of RDGBα and are associated with loss of function. Importantly, the ability of the PITPd in full-length RDGBFF/AA to rescue mutant phenotypes was significantly worse than that of the PITPd alone, indicating that an intact FFAT motif is necessary for PITPd activity in vivo Thus, the interaction between the FFAT motif and dVAP-A confers not only localization but also intramolecular regulation on lipid transfer by the PITPd of RDGBα. This article has an associated First Person interview with the first author of the paper.

Keywords: Drosophila; FFAT–VAP; Lipid transfer; Membrane contact site; Phosphoinositides.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • Eye Proteins / genetics
  • Eye Proteins / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Phospholipid Transfer Proteins / metabolism*
  • Protein Binding
  • Signal Transduction*


  • Drosophila Proteins
  • Eye Proteins
  • Membrane Proteins
  • Phospholipid Transfer Proteins
  • rdgB protein, Drosophila