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Phosphatidylinositol Phosphates Modulate STARD4 Sterol Transfer between Membranes
Author(s) -
Iaea David,
Maxfield Frederick
Publication year - 2015
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.29.1_supplement.715.9
Subject(s) - sterol , chemistry , phosphatidylinositol , membrane , biochemistry , biological membrane , organelle , plant lipid transfer proteins , biophysics , cholesterol , biology , signal transduction , gene
The steroidogenic acute regulator‐related lipid‐transfer (START) domain containing proteins are involved in several pathways of non‐vesicular trafficking of sterols. Among the soluble START proteins, STARD4 is expressed in most tissues and has previously been shown to transfer sterol. However, the mechanism of membrane interaction and sterol binding of STARD4 are unclear. The activity of two sterol transport proteins were found to be modulated by PI(4)P. This suggested a potential role of phosphatidylinositol phosphates (PIPs) to act as organelle‐specific signals that could target and modulate soluble sterol transporters such as STARD4. To investigate this, the anionic lipids of donor and acceptor liposomes were replaced with physiologic levels of individual PIPs, and STARD4 sterol transport activity was measured. Utilizing bulk phosphatidylserine (PS), STARD4 transfers 7 molecules of sterol/STARD4/minute. Interestingly, we found that PI(4,5)P 2 , only in donor membranes, and PI(5)P or PI(3,5)P 2 , only in acceptor membranes, increase STARD4 activity 10‐fold to 1 molecule of sterol/STARD4/second. The sterol transfer rate for STARD4 is relatively slow from 0‐1.5 mol% PIP, with an increase in sterol transfer rate that is maintained from 2‐10 mol%. These studies identify three membrane specific PIPs that modulate STARD4 sterol transfer activity. The increase in activity is dose‐dependent, insensitive to inhibition using soluble inositol phosphates, and maintained in membranes containing bulk anionic lipids. Physiologically, these studies suggest a mechanism of rapid vectorial transport as STARD4 extracts sterol from PI(4,5)P 2 donor membranes and delivers to PI(5)P and PI(3,5)P 2 acceptor membranes to maintain sterol homeostasis.