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Molecular determinants of the localization of the phosphatidylinositol/phosphatidic acid transfer protein, Nir2 to ER‐PM contact sites
Author(s) -
Kim Yeun Ju,
GuzmanHernandez Maria Luisa,
Wisniewski Eva,
Echeverria Nicolas,
Balla Tamas
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.660.4
Subject(s) - phosphatidic acid , phosphatidylinositol , phospholipase d , diacylglycerol kinase , microbiology and biotechnology , chemistry , phospholipase c , transport protein , pi , subcellular localization , protein–protein interaction , signal transduction , biochemistry , biology , cytoplasm , membrane , protein kinase c , phospholipid
We have recently described that Nir2, a homolog of the Drosophila RdgB protein and a mammalian phosphatidylinositol (PI) transfer protein, is required for the transfer of phosphatidic acid (PA) from the plasma membrane (PM) to the ER and for the transport of PI in the other direction at ER‐PM contact sites. Nir2, which is localized to the ER in quiescent cells, translocates to ER‐PM contacts sites upon phospholipase C (PLC) activation. Here, the transport of PI and PA in the opposite direction is critical for the maintenance of PI(4,5)P 2 levels and hence, sustains signaling during PLC action. The ER localization of Nir2 has been shown to be mediated by interaction with the ER‐resident VAP‐A and –B proteins via an FFAT domain, whereas the PM localization is induced by interaction with the lipid products of PI(4,5)P 2 hydrolysis, namely, diacylglycerol (DG) and PA. Here we investigated which part(s) of Nir2 are responsible for PM localization and how mutations in VAP‐B protein, identified in familial forms of amyotrophic lateral sclerosis (ALS or Lou‐Gehrig's disease) affect Nir2 localization in the ER. We will present data on our truncation and mutation studies addressing DG and PA recognition by Nir2 and show that mutations of VAP‐B not only cause mislocalization and aggregation of the VAP protein, but also impairs its binding to Nir2.