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Exploring the molecular mechanism of PIP2-regulated sterol transport by StarD4

PUBLISHED November 30, 2022 (DOI: https://doi.org/10.54985/peeref.2211p2727361)



Hengyi Xie1 , Ambrose Plante1 , Ekaterina Kots1 , Harel Weinstein1
  1. Weill Cornell Medicine

Conference / event

The 66th Biophysical Society Annual Meeting, February 2022 (San Fransisco, United States)

Poster summary

In subcellular cholesterol homeostasis StarD4 performs sterol-specific transfer with kinetics of pickup and delivery modulated by the phosphatidylinositol phosphate (PIP) present in the respective membranes. We study the molecular mechanism of StarD4 cholesterol (CHL) trafficking using molecular dynamics simulations. Comparing StarD4 binding to membranes containing PI(4,5)P2, PI(3,5)P2 or PS we find an allosteric pathway connecting repositioning of CHL in the binding pocket with gate opening, and different modes of lipid binding and embedding orientations of StarD4. These differences are associated with different free-energy barriers for cholesterol release, suggesting a mode of regulation of StarD4 sterol transport by PIP-subtypes recognition.


Molecular dynamics simulation, Allosteric pathway of gate opening, Trajectory analysis with N-body information theory, Trajectory analysis with rare event detection algorithms

Research areas

Biological Sciences


  1. Zhang, X., Xie, H., Iaea, D., Khelashvili, G., Weinstein, H., and Maxfield, F. R. (2022) Phosphatidylinositol Phosphates Modulate Interactions between the StarD4 Sterol Trafficking Protein and Lipid Membranes. J Biol Chem, 102058


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Supplemental files

No data provided

Additional information

Competing interests
No competing interests were disclosed.
Data availability statement
The datasets generated during and / or analyzed during the current study are available from the corresponding author on reasonable request.
Creative Commons license
Copyright © 2022 Xie et al. This is an open access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Xie, H., Plante, A., Kots, E., Weinstein, H. Exploring the molecular mechanism of PIP2-regulated sterol transport by StarD4 [not peer reviewed]. Peeref 2022 (poster).
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