Model Mechanism for Lipid Uptake by the Human STARD2/PC-TP Phosphatidylcholine Transfer Protein

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• The human StAR-related lipid transfer domain protein 2 (STARD2), also known as phosphatidylcholine (PC) transfer protein, is a key player in intracellular lipid transport.
• STARD2 is a single-domain lipid transfer protein believed to mediate the transfer of PC lipids between cellular membranes.

Purpose of the Study:

• To investigate the molecular mechanisms underlying STARD2's lipid transfer capabilities.
• To elucidate the conformational changes and interactions involved in phosphatidylcholine (PC) lipid binding and extraction by STARD2.

Main Methods:

• Extensive microsecond-long molecular dynamics (MD) simulations of STARD2 in apo and holo forms.
• Simulations conducted in the presence and absence of complex lipid bilayers.
• Free energy perturbation calculations to quantify interaction energies.

Main Results:

• MD simulations revealed ligand-dependent conformational changes in STARD2.
• Spontaneous and reproducible uptake of PC lipids into STARD2's hydrophobic cavity was observed in simulations with lipid bilayers.
• The proposed lipid extraction mechanism involves metastable states stabilized by choline-tyrosine and choline-tryptophane cation-π interactions.

Conclusions:

• Cation-π interactions, particularly PC-tyrosine interactions, significantly contribute to the affinity of PC-STARD2 metastable states (1.8–2.5 kcal/mol).
• These interactions likely lower the energy barrier for lipid desorption, facilitating efficient PC lipid transfer by STARD2.
• The findings provide molecular insights into the mechanism of lipid transfer mediated by STARD2.