RDGB? localization and function at membrane contact sites is regulated by FFAT-VAP interactions.

ABSTRACT: 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 RDGB?, a multi-domain PITP localized to membrane contact sites (MCSs), results in multiple defects during PLC signalling. Here, we report that the PITPd of RDGB? does not localize to MCSs and fails to support function during strong PLC stimulation. We show that the MCS localization of RDGB? depends on the interaction of its FFAT motif with dVAP-A. Disruption of the FFAT motif (RDGB^FF/AA) or downregulation of dVAP-A, both result in mis-localization of RDGB? and are associated with loss of function. Importantly, the ability of the PITPd in full-length RDGB^FF/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 RDGB?. This article has an associated First Person interview with the first author of the paper.

SUBMITTER: Yadav S 

PROVIDER: S-EPMC5818063 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature