Molecular differences between human liver fatty acid binding protein and its T94A variant in their unbound and lipid-bound states

D’Onofrio, Mariapina; Barracchia, Carlo Giorgio; Bortot, Andrea; Munari, Francesca; Zanzoni, Serena; Assfalg, Michael

doi:10.1016/j.bbapap.2017.06.025

Cited by 5 publications

(5 citation statements)

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“…One-dimensional 13 C-NMR experiments were performed at 37 • C to examine the carboxyl signals of [ 13 C 1 ]OLA, as described in previous work [67][68][69]. Samples contained 80 µM [ 13 C 1 ]OLA in the absence or presence of 20 µM Tau.…”

Section: Nmr Spectroscopymentioning

confidence: 99%

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau

et al. 2020

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Background: The intrinsically disordered, amyloidogenic protein Tau associates with diverse classes of molecules, including proteins, nucleic acids, and lipids. Mounting evidence suggests that fatty acid molecules could play a role in the dysfunction of this protein, however, their interaction with Tau remains poorly characterized. Methods: In a bid to elucidate the association of Tau with unsaturated fatty acids at the sub-molecular level, we carried out a variety of solution NMR experiments in combination with circular dichroism and fluorescence measurements. Our study shows that Tau4RD, the highly basic four-repeat domain of Tau, associates strongly with arachidonic and oleic acid assemblies in a high lipid/protein ratio, perturbing their supramolecular states and itself undergoing time-dependent structural adaptation. The structural signatures of Tau4RD/fatty acid aggregates appear similar for arachidonic acid and oleic acid, however, they are distinct from those of another prototypical intrinsically disordered protein, α-synuclein, when bound to these lipids, revealing protein-specific conformational adaptations. Both fatty acid molecules are found to invariably promote the self-aggregation of Tau4RD and of α-synuclein. Conclusions: This study describes the reciprocal influence that Tau4RD and fatty acids exert on their conformational states, contributing to our understanding of fundamental aspects of Tau/lipid co-assembly.

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Section: Nmr Spectroscopymentioning

confidence: 99%

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau

et al. 2020

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“…A SNP in the human Fabp1 gene coding sequence leading to a human FABP T94A substitution is the most prevalent polymorphism in the FABP family (26–38% minor allele frequency; 8.3 ± 1.9% homozygous; MAF for 1000 genomes in the NCBI dbSNP database; ALFRED database). − This T94A single-amino acid substitution has little overall effect on the overall tertiary structure − or, with the exception of that for cholesterol, the affinity for most lipidic ligands (LCFA, LCFA-CoA, lysophospholipids, and fibrates). ,, On the other hand, the T94A substitution significantly alters distal amino acid orientations and/or interactions and secondary structures differentially induced by binding of such ligands. ,, Expression of the T94A variant is associated with neutral lipid accumulation (e.g., triacylglycerides) in transfected Chang liver cells and cultured primary human hepatocytes as well as non-alcoholic fatty liver disease (NAFLD) in human subjects …”

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confidence: 99%

Endocannabinoid Interaction with Human FABP1: Impact of the T94A Variant

et al. 2017

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Using recombinant human wild-type fatty acid binding protein 1 (WT FABP1 T94T) and a variant (FABP1 T94A) protein, fluorescence binding assays, and circular dichroism, it was shown for the first time that WT FABP1 and the T94A variant each have a single, relatively hydrophobic site for binding fluorescent NBD-labeled analogues of N-arachidonoylethanolamide and 2-arachidonoylglycerol with high affinity. Most native N-acylethanolamides (NAEs) but only one 2-monoacylglycerol [i.e., 2-arachidonoylglycerol (2-AG)] displaced WT FABP1-bound fluorescently labeled endocannabinoids (ECs). While the T94A variant did not differ in affinity for AEA and most other NAEs, it exhibited a modestly higher affinity for OEA, as well as a higher affinity for 2-AG. Binding of AEA and 2-AG altered WT FABP1's secondary structure more extensively than any other previously examined ligand did. The T94A variant without a ligand was more susceptible to temperature-induced unfolding. While the T94A variant was much less sensitive to ligand (i.e., AEA or 2-AG)-induced conformational change, nevertheless binding of AEA and 2-AG significantly stabilized the T94A structure to thermal unfolding. These data provide the first evidence that ECs not only bind to but also alter the secondary structure of the human FABP1, with the latter markedly impacted by the T94A substitution, a variant strongly associated with hepatic accumulation of lipids and non-alcoholic fatty liver disease (NAFLD). Importantly, NAFLD has been associated with elevated hepatic levels of ECs and FABP1.

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“…Not surprisingly, some genetic polymorphisms make distinct contributions to the structure of Fabps and, depending on their locations, influence the ability of the variants to interact with their binding partners or to membranes. It is interesting to note that the polymorphic amino acid residues of FABP1 T94A, FABP2 A54T, FABP6 T79M, and FABP8 F57A are situated in the portal region of these Fabps 46–49 . Structural changes imparted by the altered residues on the biochemical properties of these proteins are no doubt involved in expressing their phenotypes, although how these are accomplished is not exactly known.…”

Section: Fabp Structure and Putative Functionsmentioning

confidence: 99%

“…It is interesting to note that the polymorphic amino acid residues of FABP1 T94A, FABP2 A54T, FABP6 T79M, and FABP8 F57A are situated in the portal region of these Fabps. 46 , 47 , 48 , 49 Structural changes imparted by the altered residues on the biochemical properties of these proteins are no doubt involved in expressing their phenotypes, although how these are accomplished is not exactly known. Amino acid residues in the two α helices that form the lid as well as those in the hinge and portal regions have been seen to be important in ligand selection, binding/release, and interaction with membranes but the nature and sequence of changes that results in the alteration of the metabolic programs have not yet been fully worked out.…”

Section: Fabp Structure and Putative Functionsmentioning

confidence: 99%

Importance of fatty acid binding proteins in cellular function and organismal metabolism

Agellon

2023

J Cellular Molecular Medi

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Fatty acid binding proteins (Fabps) are small soluble proteins that are abundant in the cytosol. These proteins are known to bind a myriad of small hydrophobic molecules and have been postulated to serve a variety of roles, yet their precise functions have remained an enigma over half a century of study. Here, we consider recent findings, along with the cumulative findings contributed by many laboratories working on Fabps over the last half century, to synthesize a new outlook for what functions Fabps serve in cells and organisms. Collectively, the findings illustrate that Fabps function as versatile multi‐purpose devices serving as sensors, conveyors and modulators to enable cells to detect and handle a specific class of metabolites, and to adjust their metabolic capacity and efficiency.

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Molecular differences between human liver fatty acid binding protein and its T94A variant in their unbound and lipid-bound states

Cited by 5 publications

References 30 publications

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau

Unsaturated Fatty Acid-Induced Conformational Transitions and Aggregation of the Repeat Domain of Tau

Endocannabinoid Interaction with Human FABP1: Impact of the T94A Variant

Importance of fatty acid binding proteins in cellular function and organismal metabolism

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