The Interaction of FABP with Kapα.

Area of Science:

• Molecular biology
• Biochemistry
• Structural biology

Background:

• Gene-activating lipophilic compounds enter the nucleus bound to fatty-acid-binding proteins (FABP).
• Nuclear import is mediated by the Importin system, involving α-Karyopherin (Kapα) recognizing nuclear localization signals (NLS).
• The NLS in FABP4 is cryptic, with key residues not in a continuous sequence.

Purpose of the Study:

• To clarify the mechanism of FABP4-linoleate recognition by Kapα using molecular dynamics.
• To investigate the interaction between FABP4 and Kapα, focusing on the NLS.
• To understand how FABP4-ligand complexes are prepared for nuclear transport.

Main Methods:

• Molecular dynamics simulations of Kapα complexed with NLS peptides.
• Analysis of simulated trajectories to observe structural changes and interactions.
• Generation and evaluation of docked conformations of FABP4 with Kapα.

Main Results:

• Simulated NLS peptide orientation rapidly changed, indicating dynamic interactions.
• FABP4-Kapα interactions were most extensive at the minor binding site of Kapα.
• This interaction suppressed Kapα self-inhibition, facilitating Kapβ binding.
• A transportable conformation involved an extended hydrophobic domain, allowing linoleate migration.

Conclusions:

• The FABP4-minor site interaction is crucial for Kapα activation and nuclear import.
• A specific conformation of FABP4-linoleate facilitates nuclear transport by forming a combined binding pocket with Kapα.
• This mechanism highlights the adaptability of FABP-mediated nuclear import for lipophilic compounds.