Specificity determinants for lipids bound to β-barrel proteins

Reese, Amy J.; Banaszak, Leonard J.

doi:10.1194/jlr.m300113-jlr200

Cited by 11 publications

(8 citation statements)

References 54 publications

(58 reference statements)

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“…( b ) Superposition of the complex of axolotl liver BABP with oleic acid (red) and the model of the mutant of mouse adipocyte lipid‐binding protein (ALBP, ref. 39, PDB code 1G74, blue in the figure).…”

Section: Resultsmentioning

confidence: 99%

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Crystal structure of axolotl (Ambystoma mexicanum) liver bile acid‐binding protein bound to cholic and oleic acid

et al. 2006

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The family of the liver bile acid-binding proteins (L-BABPs), formerly called liver basic fatty acid-binding proteins (Lb-FABPs) shares fold and sequence similarity with the paralogous liver fatty acid-binding proteins (L-FABPs) but has a different stoichiometry and specificity of ligand binding. This article describes the first X-ray structure of a member of the L-BABP family, axolotl (Ambystoma mexicanum) L-BABP, bound to two different ligands: cholic and oleic acid. The protein binds one molecule of oleic acid in a position that is significantly different from that of either of the two molecules that bind to rat liver FABP. The stoichiometry of binding of cholate is of two ligands per protein molecule, as observed in chicken L-BABP. The cholate molecule that binds buried most deeply into the internal cavity overlaps well with the analogous bound to chicken L-BABP, whereas the second molecule, which interacts with the first only through hydrophobic contacts, is more external and exposed to the solvent.

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Section: Resultsmentioning

confidence: 99%

“…38, PDB code 1VYF), and a triple mutant of mouse adipocyte lipid‐binding protein (ALBP, ref. 39, PDB code 1G74). Of the five proteins examined, the one that appears to bind a single oleate molecule most similarly to ax‐L‐BABP is the triple mutant of mouse ALBP.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of axolotl (Ambystoma mexicanum) liver bile acid‐binding protein bound to cholic and oleic acid

et al. 2006

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“…Like all known ligands, both linoleic acid and troglitazone bind in the internal pocket of FABP4 within a plane that is parallel with and just below the helix-turn-helix motif. 16,19 Superposition of the holo structures with the apo structure (PDB entry 1LIB) shows surprisingly little change within the backbone (Figure 1(b)). …”

Section: Structural Changes Related To Ligand Bindingmentioning

confidence: 94%

Structural Basis for Activation of Fatty Acid-binding Protein 4

Gillilan

Ayers

Noy

2007

Journal of Molecular Biology

144

153

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Fatty acid-binding protein 4 (FABP4) delivers ligands from the cytosol to the nuclear receptor PPARgamma 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.

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“…The common feature that identifies a fatty acid binding site appears to include variations on a theme of electrostatic interactions with polar and basic side chains to coordinate the carboxylate head group of the fat. It should be noted that arginine side chain interactions with fats have been observed in other protein structures with very different folds (35,38,39,40,41). The dimer interface is organized via the C-terminal region (a3, b5, and a4).…”

Section: Discussionmentioning

confidence: 99%

Three-dimensional structure/function analysis of SCP-2-like2 reveals differences among SCP-2 family members

Dyer

Wessely

Forest

et al. 2008

Journal of Lipid Research

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Mosquito sterol carrier protein-2 (AeSCP-2) and sterol carrier protein-2-like2 (AeSCP-2L2) are members of the SCP-2 protein family with similar expression profiles in the mosquito life cycle. In an effort to understand how lipids can be transported by different SCP-2 proteins, the three-dimensional crystal structure of AeSCP-2L2 was solved at 1.7 Å resolution. AeSCP-2L2 forms a dimer and binds three fatty acids, one of which resides in a position within the internal cavity at a right angle to the others. This first report of ligand-bound dimerized protein in the SCP-2 protein family indicates that the family has a much more divergent mode of interaction with ligands than previously reported. The potential function of AeSCP-2L2 was investigated via in vivo incorporation of [ 3 H]cholesterol and [ 3 H]palmitic acid. Overexpression of AeSCP-2L2 in mosquito cells leads to an increased uptake of free fatty acid, whereas knockdown of AeSCP-2L2 in adult females decreases the accumulation of free fatty acid in the fat body from a blood meal. In contrast, overexpression or knockdown of AeSCP-2L2 has no effect on cholesterol uptake. Our results suggest that the main function of AeSCP-2L2 is as a general intracellular fatty acid carrier, as opposed to having a dedicated role in cholesterol transport.-Dyer, D. H., V. Wessely, K. T. Forest, and Q. Lan. Three-dimensional structure/function analysis of SCP-2-like2 reveals differences among SCP-2 family members. J. Lipid Res. 2008. 49: 644-653.

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Specificity determinants for lipids bound to β-barrel proteins

Cited by 11 publications

References 54 publications

Crystal structure of axolotl (Ambystoma mexicanum) liver bile acid‐binding protein bound to cholic and oleic acid

Crystal structure of axolotl (Ambystoma mexicanum) liver bile acid‐binding protein bound to cholic and oleic acid

Structural Basis for Activation of Fatty Acid-binding Protein 4

Three-dimensional structure/function analysis of SCP-2-like2 reveals differences among SCP-2 family members

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