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Title: Structural Basis for Activation of Fatty Acid-binding Protein 4

Abstract

Fatty acid-binding protein 4 (FABP4) delivers ligands from the cytosol to the nuclear receptor PPAR{gamma} in the nucleus, thereby enhancing the transcriptional activity of the receptor. Notably, FABP4 binds multiple ligands with a similar affinity but its nuclear translocation is activated only by specific compounds. To gain insight into the structural features that underlie the ligand-specificity in activation of the nuclear import of FABP4, we solved the crystal structures of the protein complexed with two compounds that induce its nuclear translocation, and compared these to the apo-protein and to FABP4 structures bound to non-activating ligands. Examination of these structures indicates that activation coincides with closure of a portal loop phenylalanine side-chain, contraction of the binding pocket, a subtle shift in a helical domain containing the nuclear localization signal of the protein, and a resultant change in oligomeric state that exposes the nuclear localization signal to the solution. Comparisons of backbone displacements induced by activating ligands with a measure of mobility derived from translation, libration, screw (TLS) refinement, and with a composite of slowest normal modes of the apo state suggest that the helical motion associated with the activation of the protein is part of the repertoire of the equilibrium motionsmore » of the apo-protein, i.e. that ligand binding does not induce the activated configuration but serves to stabilize it. Nuclear import of FABP4 can thus be understood in terms of the pre-existing equilibrium hypothesis of ligand binding.« less

Authors:
; ;
Publication Date:
Research Org.:
Brookhaven National Laboratory (BNL) National Synchrotron Light Source
Sponsoring Org.:
Doe - Office Of Science
OSTI Identifier:
929974
Report Number(s):
BNL-80579-2008-JA
Journal ID: ISSN 0022-2836; JMOBAK; TRN: US200822%%1133
DOE Contract Number:  
DE-AC02-98CH10886
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Molecular Biology; Journal Volume: 372
Country of Publication:
United States
Language:
English
Subject:
36 MATERIALS SCIENCE; CARBOXYLIC ACIDS; CONFIGURATION; CRYSTAL STRUCTURE; EQUILIBRIUM; FASTENERS; HYPOTHESIS; LIGANDS; MOBILITY; MOTION; PHENYLALANINE; PROTEINS; RECEPTORS; SIGNALS; TRANSLOCATION; national synchrotron light source

Citation Formats

Gillilan,R., Ayers, S., and Noy, N. Structural Basis for Activation of Fatty Acid-binding Protein 4. United States: N. p., 2007. Web. doi:10.1016/j.jmb.2007.07.040.
Gillilan,R., Ayers, S., & Noy, N. Structural Basis for Activation of Fatty Acid-binding Protein 4. United States. doi:10.1016/j.jmb.2007.07.040.
Gillilan,R., Ayers, S., and Noy, N. Mon . "Structural Basis for Activation of Fatty Acid-binding Protein 4". United States. doi:10.1016/j.jmb.2007.07.040.
@article{osti_929974,
title = {Structural Basis for Activation of Fatty Acid-binding Protein 4},
author = {Gillilan,R. and Ayers, S. and Noy, N.},
abstractNote = {Fatty acid-binding protein 4 (FABP4) delivers ligands from the cytosol to the nuclear receptor PPAR{gamma} in the nucleus, thereby enhancing the transcriptional activity of the receptor. Notably, FABP4 binds multiple ligands with a similar affinity but its nuclear translocation is activated only by specific compounds. To gain insight into the structural features that underlie the ligand-specificity in activation of the nuclear import of FABP4, we solved the crystal structures of the protein complexed with two compounds that induce its nuclear translocation, and compared these to the apo-protein and to FABP4 structures bound to non-activating ligands. Examination of these structures indicates that activation coincides with closure of a portal loop phenylalanine side-chain, contraction of the binding pocket, a subtle shift in a helical domain containing the nuclear localization signal of the protein, and a resultant change in oligomeric state that exposes the nuclear localization signal to the solution. Comparisons of backbone displacements induced by activating ligands with a measure of mobility derived from translation, libration, screw (TLS) refinement, and with a composite of slowest normal modes of the apo state suggest that the helical motion associated with the activation of the protein is part of the repertoire of the equilibrium motions of the apo-protein, i.e. that ligand binding does not induce the activated configuration but serves to stabilize it. Nuclear import of FABP4 can thus be understood in terms of the pre-existing equilibrium hypothesis of ligand binding.},
doi = {10.1016/j.jmb.2007.07.040},
journal = {Journal of Molecular Biology},
number = ,
volume = 372,
place = {United States},
year = {Mon Jan 01 00:00:00 EST 2007},
month = {Mon Jan 01 00:00:00 EST 2007}
}